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Diketopyrrolopyrrole-based Conjugated Polymers Bearing Branched Oligo(Ethylene Glycol) Side Chains for Photovoltaic Devices.
Chen, Xingxing; Zhang, Zijian; Ding, Zicheng; Liu, Jun; Wang, Lixiang
Conjugated polymers are essential for solution-processable organic opto-electronic devices. In contrast to the great efforts on developing new conjugated polymer backbones, research on developing side chains is rare. Herein, we report branched oligo(ethylene glycol) (OEG) as side chains of conjugated polymers. Compared with typical alkyl side chains, branched OEG side chains endowed the resulting conjugated polymers with a smaller π-π stacking distance, higher hole mobility, smaller optical band gap, higher dielectric constant, and larger surface energy. Moreover, the conjugated polymers with branched OEG side chains exhibited outstanding photovoltaic performance in polymer solar cells. A power conversion efficiency of 5.37 % with near-infrared photoresponse was demonstrated and the device performance could be insensitive to the active layer thickness. PMID:27258171
Supramolecular control of self-assembling terthiophene-peptide conjugates through the amino acid side chain
Lehrman, Jessica A.; Cui, Honggang; Tsai, Wei-Wen; Moyer, Tyson J.; Stupp, Samuel I.
The self-assembly of oligothiophene–peptide conjugates can be directed through the systematic variation of the peptide sequence into different nanostructures, including flat spicules, nanotubes, spiral sheets, and giant, flat sheets. Furthermore, the assembly of these molecules is not controlled by steric interactions between the amino acid side chains.
Effects of polymer side chains on the self-assembling of conjugated polymer in thin film
NASA Astrophysics Data System (ADS)
Jiang, Yunfei; Wang, Yiqing; Bunz, Uvw H. F.; Perahia, Dvora
Conjugated polymers are inherently semi-conducting and optically active materials, with immense potential applications in organic electro-optical devices. The chemical structure of the polymer including the rigidity of the backbone and the nature of substituents affect their association as well as their electro-optical response. The following work reports the effects of different side chains on the structure and fluorescence of highly conjugated polymer, poly(para phenyleneethynylene) (PPE). When substituted by long polylactide side chains they self-assemble into wires with fingerprint-like arrangement, casting from chloroform solutions on oxidized silicon wafer. With increasing content of poor solvent, the dimension of the structures increased and then crystallized area appeared, as showed in AFM studies. The introducing of the long flexible polymer side chains has significantly reduced the stacking between rigid backbones. This in tern results in a frequency shift in their fluoresces response, indication changes in the electronic levels. Direct measurements of the electronic levels using ATM are currently in progress.
Ultrafast energy transfer from rigid, branched side-chains into a conjugated, alternating copolymer
Griffin, Graham B.; Rolczynski, Brian S.; Linkin, Alexander; McGillicuddy, Ryan D.; Engel, Gregory S.; Lundin, Pamela M.; Bao, Zhenan
We present the synthesis and characterization of a benzodithiophene/thiophene alternating copolymer decorated with rigid, singly branched pendant side chains. We characterize exciton migration and recombination dynamics in these molecules in tetrahydrofuran solution, using a combination of static and time-resolved spectroscopies. As control experiments, we also measure electronic relaxation dynamics in isolated molecular analogues of both the side chain and polymer moieties. We employ semi-empirical and time-dependent density functional theory calculations to show that photoexcitation of the decorated copolymer using 395 nm laser pulses results in excited states primarily localized on the pendant side chains. We use ultrafast transient absorption spectroscopy to show that excitations are transferred to the polymer backbone faster than the instrumental response function, ∼250 fs.
A Novel Auxin Conjugate Hydrolase from Wheat with Substrate Specificity for Longer Side-Chain Auxin Amide Conjugates1
Campanella, James J.; Olajide, Adebanke F.; Magnus, Volker; Ludwig-Müller, Jutta
This study investigates how the ILR1-like indole acetic acid (IAA) amidohydrolase family of genes has functionally evolved in the monocotyledonous species wheat (Triticum aestivum). An ortholog for the Arabidopsis IAR3 auxin amidohydrolase gene has been isolated from wheat (TaIAR3). The TaIAR3 protein hydrolyzes negligible levels of IAA-Ala and no other IAA amino acid conjugates tested, unlike its ortholog IAR3. Instead, TaIAR3 has low specificity for the ester conjugates IAA-Glc and IAA-myoinositol and high specificity for the conjugates of indole-3-butyric acid (IBA-Ala and IBA-Gly) and indole-3-propionic-acid (IPA-Ala) so far tested. TaIAR3 did not convert the methyl esters of the IBA conjugates with Ala and Gly. IBA and IBA conjugates were detected in wheat seedlings by gas chromatography-mass spectrometry, where the conjugate of IBA with Ala may serve as a natural substrate for this enzyme. Endogenous IPA and IPA conjugates were not detected in the seedlings. Additionally, crude protein extracts of wheat seedlings possess auxin amidohydrolase activity. Temporal expression studies of TaIAR3 indicate that the transcript is initially expressed at day 1 after germination. Expression decreases through days 2, 5, 10, 15, and 20. Spatial expression studies found similar levels of expression throughout all wheat tissues examined. PMID:15299127
Use of side-chain for rational design of n-type diketopyrrolopyrrole-based conjugated polymers: what did we find out?
Kanimozhi, Catherine; Yaacobi-Gross, Nir; Burnett, Edmund K; Briseno, Alejandro L; Anthopoulos, Thomas D; Salzner, Ulrike; Patil, Satish
The primary role of substituted side chains in organic semiconductors is to increase their solubility in common organic solvents. In the recent past, many literature reports have suggested that the side chains play a critical role in molecular packing and strongly impact the charge transport properties of conjugated polymers. In this work, we have investigated the influence of side-chains on the charge transport behavior of a novel class of diketopyrrolopyrrole (DPP) based alternating copolymers. To investigate the role of side-chains, we prepared four diketopyrrolopyrrole-diketopyrrolopyrrole (DPP-DPP) conjugated polymers with varied side-chains and carried out a systematic study of thin film microstructure and charge transport properties in polymer thin-film transistors (PTFTs). Combining results obtained from grazing incidence X-ray diffraction (GIXD) and charge transport properties in PTFTs, we conclude side-chains have a strong influence on molecular packing, thin film microstructure, and the charge carrier mobility of DPP-DPP copolymers. However, the influence of side-chains on optical properties was moderate. The preferential "edge-on" packing and dominant n-channel behavior with exceptionally high field-effect electron mobility values of >1 cm(2) V(-1) s(-1) were observed by incorporating hydrophilic (triethylene glycol) and hydrophobic side-chains of alternate DPP units. In contrast, moderate electron and hole mobilities were observed by incorporation of branched hydrophobic side-chains. This work clearly demonstrates that the subtle balance between hydrophobicity and hydrophilicity induced by side-chains is a powerful strategy to alter the molecular packing and improve the ambipolar charge transport properties in DPP-DPP based conjugated polymers. Theoretical analysis supports the conclusion that the side-chains influence polymer properties through morphology changes, as there is no effect on the electronic properties in the gas phase. The exceptional
Exploring the correlation between molecular conformation and optoelectronic properties of conjugated polymers : side-chain versus main-chain electron acceptors
NASA Astrophysics Data System (ADS)
Huang, Yu-Chen; Huang, Ching-I.
Polythiophene derivatives have been shown among the most promising materials for solar cell application because of their high charge mobility and light absorption. In the mostly studied, a recombination process often occurs, which is mainly due to the fact that the mobility of hole is much lower than that of electron. Hence, research about conjugated polymers containing donor-accepter pairs (such as PT-TPD) becomes quite popular because these materials have narrow band-gaps. Interestingly, these experimental studies have indicated a much more complex correlation between the optoelectronic properties and molecular conformation for polymers with acceptor units on either main or side chain. However, the effects associated with the molecular packing on the resultant chain conformation behavior and thereafter the optoelectronic properties have not been systematically discussed. In order to clarify the effects of the molecular conformation as well as the optoelectronic properties, we employ molecular dynamics and quantum mechanical methods to examine PBTTPD molecules with acceptor unit (TPD) on either main or side chain Computation resources from the National Center for High-Performance Computing of Taiwan and Computer and Information Networking Center of National Taiwan University.
Side-chain effects on the conductivity, morphology, and thermoelectric properties of self-doped narrow-band-gap conjugated polyelectrolytes.
Mai, Cheng-Kang; Schlitz, Ruth A; Su, Gregory M; Spitzer, Daniel; Wang, Xiaojia; Fronk, Stephanie L; Cahill, David G; Chabinyc, Michael L; Bazan, Guillermo C
This contribution reports a series of anionic narrow-band-gap self-doped conjugated polyelectrolytes (CPEs) with π-conjugated cyclopenta-[2,1-b;3,4-b']-dithiophene-alt-4,7-(2,1,3-benzothiadiazole) backbones, but with different counterions (Na(+), K(+), vs tetrabutylammonium) and lengths of alkyl chains (C4 vs C3). These materials were doped to provide air-stable, water-soluble conductive materials. Solid-state electrical conductivity, thermopower, and thermal conductivity were measured and compared. CPEs with smaller counterions and shorter side chains exhibit higher doping levels and form more ordered films. The smallest countercation (Na(+)) provides thin films with higher electrical conductivity, but a comparable thermopower, compared to those with larger counterions, thereby leading to a higher power factor. Chemical modifications of the pendant side chains do not influence out of plane thermal conductivity. These studies introduce a novel approach to understand thermoelectric performance by structural modifications. PMID:25179403
Side-Chain Cysteine-Functionalized Poly(2-oxazoline)s for Multiple Peptide Conjugation by Native Chemical Ligation
We prepared statistical copolymers composed of 2-methyl-2-oxazoline (MeOx) in combination with 2-butenyl-2-oxazoline (BuOx) or 2-decenyl-2-oxazoline (DecOx) as a basis for polymer analogous introduction of 1,2-aminothiol moieties at the side chain. MeOx provides hydrophilicity as well as cyto- and hemocompatibility, whereas the alkene groups of BuOx and DecOx serve for functionalization with a thiofunctional thiazolidine by UV-mediated thiol–ene reaction. After deprotection the cysteine content in functionalized poly(2-oxazoline) (POx) is quantified by NMR and a modified trinitrobenzenesulfonic acid assay. The luminescent cell viability assay shows no negative influence of cysteine-functionalized POx (cys-POx) concerning cell viability and cell number. cys-POx was used for multiple chemically orthogonal couplings with thioester-terminated peptides through native chemical ligation (NCL), which was performed and confirmed by NMR and MALDI-ToF measurements. PMID:25728550
Significant Improvement of Semiconducting Performance of the Diketopyrrolopyrrole-Quaterthiophene Conjugated Polymer through Side-Chain Engineering via Hydrogen-Bonding.
Yao, Jingjing; Yu, Chenmin; Liu, Zitong; Luo, Hewei; Yang, Yang; Zhang, Guanxin; Zhang, Deqing
Three diketopyrrolopyrrole (DPP)-quaterthiophene conjugated polymers, pDPP4T-1, pDPP4T-2, and pDPP4T-3, in which the molar ratios of the urea-containing alkyl chains vs branching alkyl chains are 1:30, 1:20, and 1:10, respectively, were prepared and investigated. In comparison with pDPP4T without urea groups in the alkyl side chains and pDPP4T-A, pDPP4T-B, and pDPP4T-C containing both linear and branched alkyl chains, thin films of pDPP4T-1, pDPP4T-2, and pDPP4T-3 exhibit higher hole mobilities; thin-film mobility increases in the order pDPP4T-1 < pDPP4T-2 < pDPP4T-3, and hole mobility of a thin film of pDPP4T-3 can reach 13.1 cm(2) V(-1) s(-1) after thermal annealing at just 100 °C. The incorporation of urea groups in the alkyl side chains also has an interesting effect on the photovoltaic performances of DPP-quaterthiophene conjugated polymers after blending with PC71BM. Blended thin films of pDPP4T-1:PC71BM, pDPP4T-2:PC71BM, and pDPP4T-3:PC71BM exhibit higher power conversion efficiencies (PCEs) than pDPP4T:PC71BM, pDPP4T-A:PC71BM, pDPP4T-B:PC71BM, and pDPP4T-C:PC71BM. The PCE of pDPP4T-1:PC71BM reaches 6.8%. Thin films of pDPP4T-1, pDPP4T-2, and pDPP4T-3 and corresponding thin films with PC71BM were characterized with AFM, GIXRD, and STEM. The results reveal that the lamellar packing order of the alkyl chains is obviously enhanced for thin films of pDPP4T-1, pDPP4T-2, and pDPP4T-3; after thermal annealing, slight inter-chain π-π stacking emerges for pDPP4T-2 and pDPP4T-3. Blends of pDPP4T-1, pDPP4T-2, and pDPP4T-3 with PC71BM show a more pronounced micro-phase separation. These observations suggest that the presence of urea groups may further facilitate the assemblies of these conjugated polymers into nanofibers and ordered aggregation of PC71BM. PMID:26669732
The effect of side-chain length on the solid-state structure and optoelectronic properties of fluorene-alt-benzothiadiazole based conjugated polymers--a DFT study.
Eslamibidgoli, Mohammad J; Lagowski, Jolanta B
Using the dispersion corrected density functional theory (DFT-D/B97D) approach, we have performed bulk solid-state calculations to investigate the influence of side-chain length on the molecular packing and optoelectronic properties of poly (9,9-di-n-alkylfluorene-alt-benzothiadiazole) or FnBT's where n is the number of CH(2) units in the alkyl side-chains. Our results indicate that the FnBT's with longer side-chains in their most stable configurations, due to the significant intermolecular interactions between the side-chains, form lamellar crystal structures. On the other hand, for the FnBT's with shorter side-chains, two nearly degenerate stable crystal structures with nearly hexagonal symmetries have been found. These different packing structures can be attributed to the microphase separations between the flexible side-chains and the rigid backbones whose existence has been discussed in previous investigations for other hairy rod polymers. As a result of the efficient interchain interactions for the lamellar structures, the dihedral angle between the F and BT units is reduced by about 30°, providing a more planar configuration for the backbone. In turn, a more planar backbone leads to a decrease, about 0.2 and 0.3 eV, of the band gaps of the lamellar structures relative to the gap values for the gas and the nearly hexagonal phases, respectively. Time-dependent DFT (TD-DFT) was used to study the excited states of the monomers of FnBT's with various lengths of side-chains. TD-DFT study suggests that the absorption spectrum of the polymers with longer side-chains is red-shifted relative to the polymers with shorter side-chains and the gas phase. PMID:23050864
Effects of Alkylthio and Alkoxy Side Chains in Polymer Donor Materials for Organic Solar Cells.
Cui, Chaohua; Wong, Wai-Yeung
Side chains play a considerable role not only in improving the solubility of polymers for solution-processed device fabrication, but also in affecting the molecular packing, electron affinity and thus the device performance. In particular, electron-donating side chains show unique properties when employed to tune the electronic character of conjugated polymers in many cases. Therefore, rational electron-donating side chain engineering can improve the photovoltaic properties of the resulting polymer donors to some extent. Here, a survey of some representative examples which use electron-donating alkylthio and alkoxy side chains in conjugated organic polymers for polymer solar cell applications will be presented. It is envisioned that an analysis of the effect of such electron-donating side chains in polymer donors would contribute to a better understanding of this kind of side chain behavior in solution-processed conjugated organic polymers for polymer solar cells. PMID:26754772
Highly Sensitive Thin-Film Field-Effect Transistor Sensor for Ammonia with the DPP-Bithiophene Conjugated Polymer Entailing Thermally Cleavable tert-Butoxy Groups in the Side Chains.
Yang, Yang; Zhang, Guanxin; Luo, Hewei; Yao, Jingjing; Liu, Zitong; Zhang, Deqing
The sensing and detection of ammonia have received increasing attention in recent years because of the growing emphasis on environmental and health issues. In this paper, we report a thin-film field-effect transistor (FET)-based sensor for ammonia and other amines with remarkable high sensitivity and satisfactory selectivity by employing the DPP-bithiophene conjugated polymer pDPPBu-BT in which tert-butoxycarboxyl groups are incorporated in the side chains. This polymer thin film shows p-type semiconducting property. On the basis of TGA and FT-IR analysis, tert-butoxycarboxyl groups can be transformed into the -COOH ones by eliminating gaseous isobutylene after thermal annealing of pDPPBu-BT thin film at 240 °C. The FET with the thermally treated thin film of pDPPBu-BT displays remarkably sensitive and selective response toward ammonia and volatile amines. This can be attributed to the fact that the elimination of gaseous isobutylene accompanies the formation of nanopores with the thin film, which will facilitate the diffusion and interaction of ammonia and other amines with the semiconducting layer, leading to high sensitivity and fast response for this FET sensor. This FET sensor can detect ammonia down to 10 ppb and the interferences from other volatile analytes except amines can be negligible. PMID:26883723
Synthesis of furanonaphthoquinones with hydroxyamino side chains.
Wu, C; Johnson, R K; Mattern, M R; Wong, J C; Kingston, D G
Several furanonaphthoquinones have shown useful activity in a yeast assay for DNA-damaging agents and cytotoxicity in mammalian cell culture assays. These results, together with the planar aromatic character of the furanonaphthoquinones, suggested that they might be acting as DNA intercalators. In an attempt to improve this activity, various analogues containing a hydroxyamino side chain have been synthesized. The analogues were prepared by standard methods, but some unexpected reactions were observed nonetheless. Thus, 8-formyl-5-methoxy-4,9-dihydronaphtho[2,3-b]furan-4,9-dione (24) showed an unusual reactivity toward reductive amination, with the reaction proceeding further to give one of two different cyclized products, depending on the amination reagent used. Bioassay results indicated that only simple furanonaphthoquines showed activity in a yeast assay for DNA-damaging agents; compounds with a substituted hydroxyamino side chain were uniformly inactive in this assay. Most of the compounds with a substituted hydroxyamino side chain on the furan ring did, however, show cytotoxicity, although none of them was any more active than the simple aldehyde 2-formyl-4, 9-dihydronaphtho[2,3-b]furan-4,9-dione (14). This evidence tends to suggest that the furanonaphthoquinones do not serve primarily as DNA intercalators, because if this were the case, they would have been expected to show an increased activity on conversion to their hydroxyamino side chain derivatives. PMID:10425117
Peptide nanotube aligning side chains onto one side.
Tabata, Yuki; Mitani, Shota; Kimura, Shunsaku
A novel pseudo cyclic penta-β-peptide composed of a β-naphthylalanine, two β-alanines, and a sequence of ethylenediamine-succinic acid (CP5ES) is synthesized and investigated on peptide nanotube (PNT) formation. When the PNT is formed with the maximum number of intermolecular hydrogen bonds between the cyclic peptides, the sequence enables the alignment of the side chains, naphthyl groups, on one side of the PNT. Microscopic and spectroscopic observations of CP5ES crystals reveal that CP5ES forms rod- or needle-shaped molecular assemblies showing exciton coupling of the Cotton effect and predominant monomer emission, which are different from a reference cyclic tri-β-peptide composed of a β-naphthylalanine and two β-alanines. Insertion of a sequence of ethylenediamine-succinic acid into β-amino acids in the cyclic skeleton is therefore suggested to be effective to make the side chains aligning on one side of the PNT. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27282135
Helical folding of conjugated oligo(phenyleneethynylene): chain-length dependence, solvent effects, and intermolecular assembly.
Zhu, Ningbo; Yan, Qifan; Luo, Zhouyang; Zhai, You; Zhao, Dahui
As a representative folding system that features a conjugated backbone, a series of monodispersed (o-phenyleneethynylene)-alt-(p-phenyleneethynylene) (PE) oligomers of varied chain length and different side chains were studied. Molecules with the same backbone but different side-chain structures were shown to exhibit similar helical conformations in respectively suitable solvents. Specifically, oligomers with dodecyloxy side chains folded into the helical structure in apolar aliphatic solvents, whereas an analogous oligomer with tri(ethylene glycol) (Tg) side chains adopted the same conformation in polar solvents. The fact that the oligomers with the same backbone manifested a similar folded conformation independent of side chains and the nature of the solvent confirmed the concept that the driving force for folding was the intramolecular aromatic stacking and solvophobic interactions. Although all were capable of inducing folding, different solvents were shown to bestow slightly varied folding stability. The chain-length dependence study revealed a nonlinear correlation between the folding stability with backbone chain length. A critical size of approximately 10 PE units was identified for the system, beyond which folding occurred. This observation corroborated the helical nature of the folded structure. Remarkably, based on the absorption and emission spectra, the effective conjugation length of the system extended more effectively under the folded state than under random conformations. Moreover, as evidenced by the optical spectra and dynamic light-scattering studies, intermolecular association took place among the helical oligomers with Tg side chains in aqueous solution. The demonstrated ability of such a conjugated foldamer in self-assembling into hierarchical supramolecular structures promises application potential for the system. PMID:22829335
SCit: web tools for protein side chain conformation analysis.
Gautier, R; Camproux, A-C; Tufféry, P
SCit is a web server providing services for protein side chain conformation analysis and side chain positioning. Specific services use the dependence of the side chain conformations on the local backbone conformation, which is described using a structural alphabet that describes the conformation of fragments of four-residue length in a limited library of structural prototypes. Based on this concept, SCit uses sets of rotameric conformations dependent on the local backbone conformation of each protein for side chain positioning and the identification of side chains with unlikely conformations. The SCit web server is accessible at http://bioserv.rpbs.jussieu.fr/SCit. PMID:15215438
Microwave-assisted solid-phase synthesis of side-chain to side-chain lactam-bridge cyclic peptides.
Tala, Srinivasa R; Schnell, Sathya M; Haskell-Luevano, Carrie
Side-chain to side-chain lactam-bridged cyclic peptides have been utilized as therapeutic agents and biochemical tools. Previous synthetic methods of these peptides need special reaction conditions, form side products and take longer reaction times. Herein, an efficient microwave-assisted synthesis of side-chain to side-chain lactam-bridge cyclic peptides SHU9119 and MTII is reported. The synthesis time and efforts are significantly reduced in the present method, without side product formation. The analytical and pharmacological data of the synthesized cyclic peptides are in accordance with the commercially obtained compounds. This new method could be used to synthesize other side-chain to side-chain lactam-bridge peptides and amenable to automation and extensive SAR compound derivatization. PMID:26555357
Side-chain entropy and packing in proteins.
Bromberg, S; Dill, K A
What role does side-chain packing play in protein stability and structure? To address this question, we compare a lattice model with side chains (SCM) to a linear lattice model without side chains (LCM). Self-avoiding configurations are enumerated in 2 and 3 dimensions exhaustively for short chains and by Monte Carlo sampling for chains up to 50 main-chain monomers long. This comparison shows that (1) side-chain degrees of freedom increase the entropy of open conformations, but side-chain steric exclusion decreases the entropy of compact conformations, thus producing a substantial entropy that opposes folding; (2) there is side-chain "freezing" or ordering, i.e., a sharp decrease in entropy, near maximum compactness; and (3) the different types of contacts among side chains (s) and main-chain elements (m) have different frequencies, and the frequencies have different dependencies on compactness. mm contacts contribute significantly only at high densities, suggesting that main-chain hydrogen bonding in proteins may be promoted by compactness. The distributions of mm, ms, and ss contacts in compact SCM configurations are similar to the distributions in protein structures in the Brookhaven Protein Data Bank. We propose that packing in proteins is more like the packing of nuts and bolts in a jar than like the pairwise matching of jigsaw puzzle pieces. PMID:7920265
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Protein side chain conformation predictions with an MMGBSA energy function.
Gaillard, Thomas; Panel, Nicolas; Simonson, Thomas
The prediction of protein side chain conformations from backbone coordinates is an important task in structural biology, with applications in structure prediction and protein design. It is a difficult problem due to its combinatorial nature. We study the performance of an "MMGBSA" energy function, implemented in our protein design program Proteus, which combines molecular mechanics terms, a Generalized Born and Surface Area (GBSA) solvent model, with approximations that make the model pairwise additive. Proteus is not a competitor to specialized side chain prediction programs due to its cost, but it allows protein design applications, where side chain prediction is an important step and MMGBSA an effective energy model. We predict the side chain conformations for 18 proteins. The side chains are first predicted individually, with the rest of the protein in its crystallographic conformation. Next, all side chains are predicted together. The contributions of individual energy terms are evaluated and various parameterizations are compared. We find that the GB and SA terms, with an appropriate choice of the dielectric constant and surface energy coefficients, are beneficial for single side chain predictions. For the prediction of all side chains, however, errors due to the pairwise additive approximation overcome the improvement brought by these terms. We also show the crucial contribution of side chain minimization to alleviate the rigid rotamer approximation. Even without GB and SA terms, we obtain accuracies comparable to SCWRL4, a specialized side chain prediction program. In particular, we obtain a better RMSD than SCWRL4 for core residues (at a higher cost), despite our simpler rotamer library. Proteins 2016; 84:803-819. © 2016 Wiley Periodicals, Inc. PMID:26948696
Protein-ligand docking with multiple flexible side chains.
Zhao, Yong; Sanner, Michel F
In this work, we validate and analyze the results of previously published cross docking experiments and classify failed dockings based on the conformational changes observed in the receptors. We show that a majority of failed experiments (i.e. 25 out of 33, involving four different receptors: cAPK, CDK2, Ricin and HIVp) are due to conformational changes in side chains near the active site. For these cases, we identify the side chains to be made flexible during docking calculation by superimposing receptors and analyzing steric overlap between various ligands and receptor side chains. We demonstrate that allowing these side chains to assume rotameric conformations enables the successful cross docking of 19 complexes (ligand all atom RMSD < 2.0 A) using our docking software FLIPDock. The number of side receptor side chains interacting with a ligand can vary according to the ligand's size and shape. Hence, when starting from a complex with a particular ligand one might have to extend the region of potential interacting side chains beyond the ones interacting with the known ligand. We discuss distance-based methods for selecting additional side chains in the neighborhood of the known active site. We show that while using the molecular surface to grow the neighborhood is more efficient than Euclidian-distance selection, the number of side chains selected by these methods often remains too large and additional methods for reducing their count are needed. Despite these difficulties, using geometric constraints obtained from the network of bonded and non-bonded interactions to rank residues and allowing the top ranked side chains to be flexible during docking makes 22 out of 25 complexes successful. PMID:18034309
Highly Ordered Single Conjugated Polymer Chain Rod Morphologies
Adachi, Takuji; Brazard, Johanna; Chokshi, Paresh; Ganesan, Venkat; Bolinger, Joshua; Barbara, Paul F.
We have reexamined the fluorescence polarization anisotropy of single polymer chains of the prototypical conjugated polymer poly[2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) isolated in a poly(methyl methacrylate) (PMMA) matrix employing improved synthetic samples that contain a much smaller number of tetrahedral chemical defects per chain. The new measurements reveal a much larger fraction of highly anisotropic MEH-PPV chains, with >70% of the chains exhibiting polarization anisotropy values falling in the range of 0.6-0.9. High anisotropy is strong evidence for a rod-shaped conformation. A comparison of the experimental results with coarse grain, beads on a chain simulations reveals that simulations with the usual bead-bead pairwise additive potentials cannot reproduce the observed large fraction of high polarization values. Apparently, this type of potential lacks some yet to be identified molecular feature that is necessary to accurately simulate the experimental results.
Ionizable Side Chains at Catalytic Active Sites of Enzymes
Jimenez-Morales, David; Liang, Jie
Catalytic active sites of enzymes of known structure can be well defined by a modern program of computational geometry. The CASTp program was used to define and measure the volume of the catalytic active sites of 573 enzymes in the Catalytic Site Atlas database. The active sites are identified as catalytic because the amino acids they contain are known to participate in the chemical reaction catalyzed by the enzyme. Acid and base side chains are reliable markers of catalytic active sites. The catalytic active sites have 4 acid and 5 base side chains, in an average volume of 1072 Å3. The number density of acid side chains is 8.3 M (in chemical units); the number density of basic side chains is 10.6 M. The catalytic active site of these enzymes is an unusual electrostatic and steric environment in which side chains and reactants are crowded together in a mixture more like an ionic liquid than an ideal infinitely dilute solution. The electrostatics and crowding of reactants and side chains seems likely to be important for catalytic function. In three types of analogous ion channels, simulation of crowded charges accounts for the main properties of selectivity measured in a wide range of solutions and concentrations. It seems wise to use mathematics designed to study interacting complex fluids when making models of the catalytic active sites of enzymes. PMID:22484856
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Affinity enhancement by dendritic side chains in synthetic carbohydrate receptors.
Destecroix, Harry; Renney, Charles M; Mooibroek, Tiddo J; Carter, Tom S; Stewart, Patrick F N; Crump, Matthew P; Davis, Anthony P
Dendritic side chains have been used to modify the binding environment in anthracene-based synthetic carbohydrate receptors. Control of length, charge, and branching enabled the positioning of side-chain carboxylate groups in such a way that they assisted in binding substrates rather than blocking the cavity. Conformational degeneracy in the dendrimers resulted in effective preorganization despite the flexibility of the system. Strong binding was observed to glucosammonium ions in water, with Ka values up to 7000 M(-1) . Affinities for uncharged substrates (glucose and N-acetylglucosamine) were also enhanced, despite competition from solvent and the absence of electrostatic interactions. PMID:25645064
Effect of protein crystal hydration on side chain conformational heterogeneity
NASA Astrophysics Data System (ADS)
Atakisi, Hakan; Moreau, David; Hopkins, Jesse; Thorne, Robert; Robert Thorne's group Team
The structure of protein crystals is determined in part by water-mediated interactions involving both protein surface-ordered (hydration) and bulk water, and so is sensitive to the relative humidity of the environment. Monoclinic lysozyme provides a remarkable model for studying structural changes induced by dehydration, as it maintains excellent order for relative humidities (r.h.) down to 5%, corresponding to solvent content of 9% by volume, much smaller than the 88% (22% by volume) at which lysozyme loses its enzymatic activity. Although the main chain conformation does not change significantly, the effect of dehydration on side chain conformations has not been systematically studied. High resolution (1.1 to 1.7 A) structural data sets for monoclinic lysozyme at r.h. between 99% and 11% have been analyzed to identify major and minor side chain conformers at each humidity, and to map out how the side chain conformational ensemble evolves with hydration. Modest dehydration produces comparable overall effects to cooling to T =100 K, but with conformational changes largely confined to solvent-exposed residues. The largest side chain conformation changes occur at humidities that deplete water within the first two hydration shells.
Mechanism of Polyubiquitin Chain Recognition by the Human Ubiquitin Conjugating Enzyme Ube2g2*
Bocik, William E.; Sircar, Aroop; Gray, Jeffrey J.; Tolman, Joel R.
Ube2g2 is a human ubiquitin conjugating (E2) enzyme involved in the endoplasmic reticulum-associated degradation pathway, which is responsible for the identification and degradation of unfolded and misfolded proteins in the endoplasmic reticulum compartment. The Ube2g2-specific role is the assembly of Lys-48-linked polyubiquitin chains, which constitutes a signal for proteasomal degradation when attached to a substrate protein. NMR chemical shift perturbation and paramagnetic relaxation enhancement approaches were employed to characterize the binding interaction between Ube2g2 and ubiquitin, Lys-48-linked diubiquitin, and Lys-63-linked diubiquitin. Results demonstrate that ubiquitin binds to Ube2g2 with an affinity of 90 μm in two different orientations that are rotated by 180° in models generated by the RosettaDock modeling suite. The binding of Ube2g2 to Lys-48- and Lys-63-linked diubiquitin is primarily driven by interactions with individual ubiquitin subunits, with a clear preference for the subunit containing the free Lys-48 or Lys-63 side chain (i.e. the distal subunit). This preference is particularly striking in the case of Lys-48-linked diubiquitin, which exhibits an ∼3-fold difference in affinities between the two ubiquitin subunits. This difference can be attributed to the partial steric occlusion of the subunit whose Lys-48 side chain is involved in the isopeptide linkage. As such, these results suggest that Lys-48-linked polyubiquitin chains may be designed to bind certain proteins like Ube2g2 such that the terminal ubiquitin subunit carrying the reactive Lys-48 side chain can be positioned properly for chain elongation regardless of chain length. PMID:21098018
Improved packing of protein side chains with parallel ant colonies
Introduction The accurate packing of protein side chains is important for many computational biology problems, such as ab initio protein structure prediction, homology modelling, and protein design and ligand docking applications. Many of existing solutions are modelled as a computational optimisation problem. As well as the design of search algorithms, most solutions suffer from an inaccurate energy function for judging whether a prediction is good or bad. Even if the search has found the lowest energy, there is no certainty of obtaining the protein structures with correct side chains. Methods We present a side-chain modelling method, pacoPacker, which uses a parallel ant colony optimisation strategy based on sharing a single pheromone matrix. This parallel approach combines different sources of energy functions and generates protein side-chain conformations with the lowest energies jointly determined by the various energy functions. We further optimised the selected rotamers to construct subrotamer by rotamer minimisation, which reasonably improved the discreteness of the rotamer library. Results We focused on improving the accuracy of side-chain conformation prediction. For a testing set of 442 proteins, 87.19% of X1 and 77.11% of X12 angles were predicted correctly within 40° of the X-ray positions. We compared the accuracy of pacoPacker with state-of-the-art methods, such as CIS-RR and SCWRL4. We analysed the results from different perspectives, in terms of protein chain and individual residues. In this comprehensive benchmark testing, 51.5% of proteins within a length of 400 amino acids predicted by pacoPacker were superior to the results of CIS-RR and SCWRL4 simultaneously. Finally, we also showed the advantage of using the subrotamers strategy. All results confirmed that our parallel approach is competitive to state-of-the-art solutions for packing side chains. Conclusions This parallel approach combines various sources of searching intelligence and energy
A sterol with an unusual side chain from Anoectochilus koshunensis.
Ito, A; Yasumoto, K; Kasai, R; Yamasaki, K
A new sterol with a non-conventional side chain has been isolated from the whole plant of Anoectochilus koshunensis, together with four known sterols, a megastigmane glucoside and 2'-deoxyadenosine. The structure of the new sterol was elucidated as 26-methylstigmasta-5,22,25, (27)-trien-3 beta-ol based on chemical and detailed spectroscopic evidence. PMID:7765430
Sub-cellular internalization and organ specific oral elivery of PABA nanoparticles by side chain variation
Background Organic nanomaterials having specific biological properties play important roles in in vivo delivery and clearance from the live cells. To develop orally deliverable nanomaterials for different biological applications, we have synthesized several fluorescently labelled, self-assembled PABA nanoparticles using possible acid side chain combinations and tested against insect and human cell lines and in vivo animal model. Flurophores attached to nanostructures help in rapid in vivo screening and tracking through complex tissues. The sub-cellular internalization mechanism of the conjugates was determined. A set of physio-chemical parameters of engineered nanoskeletons were also defined that is critical for preferred uptake in multiple organs of live Drosophila. Results The variability of side chains alter size, shape and surface texture of each nanomaterial that lead to differential uptake in human and insect cells and to different internal organs in live Drosophila via energy dependent endocytosis. Our results showed that physical and chemical properties of C-11 and C-16 acid chain are best fitted for delivery to complex organs in Drosophila. However a distinct difference in uptake of same nanoparticle in human and insect cells postulated that different host cell physiology plays a critical role in the uptake mechanism. Conclusions The physical and chemical properties of the nanoparticle produced by variation in the acid side chains that modify size and shape of engineered nanostructure and their interplay with host cell physiology might be the major criteria for their differential uptake to different internal organs. PMID:21443763
Selective cleavage enhanced by acetylating the side chain of lysine.
Fu, Leixiaomeng; Chen, Tingting; Xue, Gaiqing; Zu, Lily; Fang, Weihai
Selective cleavage is of great interest in mass spectrometry studies as it can help sequence identification by promoting simple fragmentation pattern of peptides and proteins. In this work, the collision-induced dissociation of peptides containing internal lysine and acetylated lysine residues were studied. The experimental and computational results revealed that multiple fragmentation pathways coexisted when the lysine residue was two amino acid residues away from N-terminal of the peptide. After acetylation of the lysine side-chain, b(n)+ ions were the most abundant primary fragment products and the Lys(Ac)-Gly amide bond became the dominant cleavage site via an oxazolone pathway. Acetylating the side-chain of lysine promoted the selective cleavage of Lys-Xxx amide bond and generated much more information of the peptide backbone sequence. The results re-evaluate the selective cleavage due to the lysine basic side-chain and provide information for studying the post-translational modification of proteins and other bio-molecules containing Lys residues. PMID:23303756
Highly conductive side chain block copolymer anion exchange membranes.
Wang, Lizhu; Hickner, Michael A
Block copolymers based on poly(styrene) having pendent trimethyl styrenylbutyl ammonium (with four carbon ring-ionic group alkyl linkers) or benzyltrimethyl ammonium groups with a methylene bridge between the ring and ionic group were synthesized by reversible addition-fragmentation radical (RAFT) polymerization as anion exchange membranes (AEMs). The C4 side chain polymer showed a 17% increase in Cl(-) conductivity of 33.7 mS cm(-1) compared to the benzyltrimethyl ammonium sample (28.9 mS cm(-1)) under the same conditions (IEC = 3.20 meq. g(-1), hydration number, λ = ∼7.0, cast from DMF/1-propanol (v/v = 3 : 1), relative humidity = 95%). As confirmed by small angle X-ray scattering (SAXS), the side chain block copolymers with tethered ammonium cations showed well-defined lamellar morphologies and a significant reduction in interdomain spacing compared to benzyltrimethyl ammonium containing block copolymers. The chemical stabilities of the block copolymers were evaluated under severe, accelerated conditions, and degradation was observed by (1)H NMR. The block copolymer with C4 side chain trimethyl styrenylbutyl ammonium motifs displayed slightly improved stability compared to that of a benzyltrimethyl ammonium-based AEM at 80 °C in 1 M NaOD aqueous solution for 30 days. PMID:27216558
Main chain and side chain dynamics of oxidized flavodoxin from Cyanobacterium anabaena.
Liu, W; Flynn, P F; Fuentes, E J; Kranz, J K; McCormick, M; Wand, A J
Oxidized flavodoxin from Cyanobacterium anabaena PCC 7119 is used as a model system to investigate the fast internal dynamics of a flavin-bearing protein. Virtually complete backbone and side chain resonance NMR assignments of an oxidized flavodoxin point mutant (C55A) have been determined. Backbone and side chain dynamics in flavodoxin (C55A) were investigated using (15)N amide and deuterium methyl NMR relaxation methods. The squared generalized order parameters (S(NH)(2)) for backbone amide N-H bonds are found to be uniformly high (
approximately 0.923 over 109 residues in regular secondary structure), indicating considerable restriction of motion in the backbone of the protein. In contrast, methyl-bearing side chains are considerably heterogeneous in their amplitude of motion, as indicated by obtained symmetry axis squared generalized order parameters (S(axis)(2)). However, in comparison to nonprosthetic group-bearing proteins studied with these NMR relaxation methods, the side chains of oxidized flavodoxin are unusually rigid. PMID:11732893
Applying Side-chain Flexibility in Motifs for Protein Docking
Liu, Hui; Lin, Feng; Yang, Jian-Li; Wang, Hong-Rui; Liu, Xiu-Ling
Conventional rigid docking algorithms have been unsatisfactory in their computational results, largely due to the fact that protein structures are flexible in live environments. In response, we propose to introduce the side-chain flexibility in protein motif into the docking. First, the Morse theory is applied to curvature labeling and surface region growing, for segmentation of the protein surface into smaller patches. Then, the protein is described by an ensemble of conformations that incorporate the flexibility of interface side chains and are sampled using rotamers. Next, a 3D rotation invariant shape descriptor is proposed to deal with the flexible motifs and surface patches; thus, pairwise complementarity matching is needed only between the convex patches of ligand and the concave patches of receptor. The iterative closest point (ICP) algorithm is implemented for geometric alignment of the two 3D protein surface patches. Compared with the fast Fourier transform-based global geometric matching algorithm and other methods, our FlexDock system generates much less false-positive docking results, which benefits identification of the complementary candidates. Our computational experiments show the advantages of the proposed flexible docking algorithm over its counterparts. PMID:26508871
Purification and characterization of corticosteroid side chain isomerase
Marandici, A.; Monder, C. )
Corticosteroid side chain isomerase of rat liver catalyzes the interconversion of the ketol (20-oxo-21-ol) and (20-hydroxy-21-al) forms of the corticosteroid side chain. The enzyme has now been purified to apparent homogeneity from rat liver cytosol by sequential chromatography on anionic, hydroxylapatite, and gel filtration columns. Ketol-aldol isomerization is followed by measuring the exchange of tritium from 21-tritiated steroids with water. The native enzyme is a dimer of MW 44,000. The isoelectric point is 4.8 {plus minus} 0.1 pH units. The purified enzyme is stimulated by Co{sup 3+} or Ni{sup 2+}. The enzyme utilizes 11-deoxycorticosterone, corticosterone, and 17-deoxycortisol as substrate but not cortisol, tetrahydrocortisol, and prednisolone. Tritium-water exchange of (21S)-(21-{sup 3}H)DOC is a pseudo-first-order reaction; 21-{sup 3}H exchange from the 21R isomer proceeds with first-order kinetics only after a lag associated with its epimerization to the 21S form.
Applying Side-chain Flexibility in Motifs for Protein Docking.
Liu, Hui; Lin, Feng; Yang, Jian-Li; Wang, Hong-Rui; Liu, Xiu-Ling
Conventional rigid docking algorithms have been unsatisfactory in their computational results, largely due to the fact that protein structures are flexible in live environments. In response, we propose to introduce the side-chain flexibility in protein motif into the docking. First, the Morse theory is applied to curvature labeling and surface region growing, for segmentation of the protein surface into smaller patches. Then, the protein is described by an ensemble of conformations that incorporate the flexibility of interface side chains and are sampled using rotamers. Next, a 3D rotation invariant shape descriptor is proposed to deal with the flexible motifs and surface patches; thus, pairwise complementarity matching is needed only between the convex patches of ligand and the concave patches of receptor. The iterative closest point (ICP) algorithm is implemented for geometric alignment of the two 3D protein surface patches. Compared with the fast Fourier transform-based global geometric matching algorithm and other methods, our FlexDock system generates much less false-positive docking results, which benefits identification of the complementary candidates. Our computational experiments show the advantages of the proposed flexible docking algorithm over its counterparts. PMID:26508871
Differential DNA and RNA sequence discrimination by PNA having charged side chains.
De Costa, N Tilani S; Heemstra, Jennifer M
PNA sequences modified with charged side chains were evaluated for base-pairing sequence selectivity under physiological conditions. PNA having negatively charged aspartic acid side chains shows higher selectivity with RNA, while PNA having positively charged lysine side chains shows higher selectivity with DNA. These observations provide insight into the binding selectivity of modified PNA in antisense and antigene applications. PMID:24731279
Co-crystallization phase transformations in all π-conjugated block copolymers with different main-chain moieties.
Lee, Yi-Huan; Chen, Wei-Chih; Yang, Yi-Lung; Chiang, Chi-Ju; Yokozawa, Tsutomu; Dai, Chi-An
Driven by molecular affinity and balance in the crystallization kinetics, the ability to co-crystallize dissimilar yet self-crystallizable blocks of a block copolymer (BCP) into a uniform domain may strongly affect its phase diagram. In this study, we synthesize a new series of crystalline and monodisperse all-π-conjugated poly(2,5-dihexyloxy-p-phenylene)-b-poly(3-(2-ethylhexyl)thiophene) (PPP-P3EHT) BCPs and investigate this multi-crystallization effect. Despite vastly different side-chain and main-chain structures, PPP and P3EHT blocks are able to co-crystallize into a single uniform domain comprising PPP and P3EHT main-chains with mutually interdigitated side-chains spaced in-between. With increasing P3EHT fraction, PPP-P3EHTs undergo sequential phase transitions and form hierarchical superstructures including predominately PPP nanofibrils, co-crystalline nanofibrils, a bilayer co-crystalline/pure P3EHT lamellar structure, a microphase-separated bilayer PPP-P3EHT lamellar structure, and finally P3EHT nanofibrils. In particular, the presence of the new co-crystalline lamellar structure is the manifestation of the interaction balance between self-crystallization and co-crystallization of the dissimilar polymers on the resulting nanostructure of the BCP. The current study demonstrates the co-crystallization nature of all-conjugated BCPs with different main-chain moieties and may provide new guidelines for the organization of π-conjugated BCPs for future optoelectronic applications. PMID:24681573
Tuning the electronic coupling in a low-bandgap donor-acceptor copolymer via the placement of side-chains
Oberhumer, Philipp M.; Huang, Ya-Shih; Massip, Sylvain; Albert-Seifried, Sebastian; Greenham, Neil C.; Hodgkiss, Justin M.; Friend, Richard H.; James, David T.; Kim, Ji-Seon; Tu Guoli; Huck, Wilhelm T. S.; Beljonne, David; Cornil, Jerome
We present a spectroscopic and theoretical investigation of the effect of the presence and position of hexyl side-chains in the novel low-bandgap alternating donor-acceptor copolymer poly[bis-N,N-(4-octylphenyl)-bis-N,N-phenyl-1, 4-phenylenediamine-alt-5,5'-4',7',-di-2-thienyl-2',1',3'-benzothiadiazole] (T8TBT). We use electronic absorption and Raman spectroscopic measurements supported by calculations of chain conformation, electronic transitions, and Raman modes. Using these tools, we find that sterically demanding side-chain configurations induce twisting in the electronic acceptor unit and reduce the electronic interaction with the donor. This leads to a blue-shifted and weakened (partial) charge-transfer absorption band together with a higher photoluminescence efficiency. On the other hand, sterically relaxed side-chain configurations promote coupling between donor and acceptor units and exhibit enhanced absorption at the expense of luminescence efficiency. The possibility of tuning the donor-acceptor character of conjugated polymers by varying the placement of side-chains has very important ramifications for light emitting diode, Laser, display, and photovoltaic device optimization.
Metabolic Glycoengineering with N-Acyl Side Chain Modified Mannosamines.
Wratil, Paul R; Horstkorte, Rüdiger; Reutter, Werner
In metabolic glycoengineering (MGE), cells or animals are treated with unnatural derivatives of monosaccharides. After entering the cytosol, these sugar analogues are metabolized and subsequently expressed on newly synthesized glycoconjugates. The feasibility of MGE was first discovered for sialylated glycans, by using N-acyl-modified mannosamines as precursor molecules for unnatural sialic acids. Prerequisite is the promiscuity of the enzymes of the Roseman-Warren biosynthetic pathway. These enzymes were shown to tolerate specific modifications of the N-acyl side chain of mannosamine analogues, for example, elongation by one or more methylene groups (aliphatic modifications) or by insertion of reactive groups (bioorthogonal modifications). Unnatural sialic acids are incorporated into glycoconjugates of cells and organs. MGE has intriguing biological consequences for treated cells (aliphatic MGE) and offers the opportunity to visualize the topography and dynamics of sialylated glycans in vitro, ex vivo, and in vivo (bioorthogonal MGE). PMID:27435524
Effect of Side Chains on Molecular Conformation of Anthracene-Ethynylene-Phenylene-Vinylene Oligomers: A Comparative Density Functional Study With and Without Dispersion Interaction.
Dong, Chuanding; Hoppe, Harald; Beenken, Wichard J D
Using density functional calculations with and without dispersion interaction, we studied the effects of linear octyl and branched 2-ethylhexyl side chains on the oligomer conformation of the conjugated copolymer poly(p-anthracene-ethynylene)-alt-poly(p-phenylene-vinylene). With dispersion included, the branched side chains can cause significant bending of the oligomer backbone, while without dispersion they induce mainly torsional disorder. The oligomers with mainly linear side chains keep good planarity when optimized with and without dispersion. Despite their dramatically different conformations, the calculated absorption spectra of the oligomers with various side chain combinations are very similar, indicating that the conformation of the copolymer is not the main reason for the experimentally observed different spectra of ordered and disordered phases. PMID:27163652
Changes in conformational dynamics of basic side chains upon protein-DNA association.
Esadze, Alexandre; Chen, Chuanying; Zandarashvili, Levani; Roy, Sourav; Pettitt, B Montgometry; Iwahara, Junji
Basic side chains play major roles in recognition of nucleic acids by proteins. However, dynamic properties of these positively charged side chains are not well understood. In this work, we studied changes in conformational dynamics of basic side chains upon protein-DNA association for the zinc-finger protein Egr-1. By nuclear magnetic resonance (NMR) spectroscopy, we characterized the dynamics of all side-chain cationic groups in the free protein and in the complex with target DNA. Our NMR order parameters indicate that the arginine guanidino groups interacting with DNA bases are strongly immobilized, forming rigid interfaces. Despite the strong short-range electrostatic interactions, the majority of the basic side chains interacting with the DNA phosphates exhibited high mobility, forming dynamic interfaces. In particular, the lysine side-chain amino groups exhibited only small changes in the order parameters upon DNA-binding. We found a similar trend in the molecular dynamics (MD) simulations for the free Egr-1 and the Egr-1-DNA complex. Using the MD trajectories, we also analyzed side-chain conformational entropy. The interfacial arginine side chains exhibited substantial entropic loss upon binding to DNA, whereas the interfacial lysine side chains showed relatively small changes in conformational entropy. These data illustrate different dynamic characteristics of the interfacial arginine and lysine side chains. PMID:27288446
Polymer side-chains as arms for molecular recognition
NASA Astrophysics Data System (ADS)
South, Clinton Ray
This thesis describes research based on synthetic protocols, methodologies, and applications of polymers containing side-chain molecular recognition elements. The motivation for the thesis lies in the belief among many in the field that a strict covalent paradigm for polymer chemistry is reaching its limit. The use of molecular recognition, in lieu of covalent chemistry, potentially presents a path through the current limits of polymer science. The work described in the following chapters of this thesis is, at least in part, a testament to this proposal. The first two chapters present a basic introduction and survey of the fundamental noncovalent interactions that are ubiquitous in the research of supramolecular polymers and molecular recognition. A hierarchy of noncovalent interactions, molecular recognition, and self-assembly is outlined and discussed. Chapter 2 lays the foundation for the remaining chapters of this thesis by presenting several examples of prior work related specifically to the use of molecular recognition on the side-chains of polymers. The next two chapters present research focused on advancing the functionalization of polymers through molecular recognition. The goal of this research is primarily to develop a general polymer backbone that both site-specifically and strongly associates noncovalently with small molecular substrates. These chapters demonstrate that both architecturally controlled block copolymers and random terpolymers can accept a full load of different substrates without interference among distinct molecular recognition elements along the polymer backbone. Chapters 5 and 6 present a unique application of polymers containing molecular recognition elements, templated synthesis. Chapter 5 first discusses lessons learned from small molecule based templated synthesis in which a template and a substrate are held together by metal coordination and a subsequent bond forming reaction occurs. Ultimately, the results of this chapter
Basic amino-acid side chains regulate transmembrane integrin signalling.
Kim, Chungho; Schmidt, Thomas; Cho, Eun-Gyung; Ye, Feng; Ulmer, Tobias S; Ginsberg, Mark H
Side chains of Lys/Arg near transmembrane domain (TMD) membrane-water interfaces can 'snorkel', placing their positive charge near negatively charged phospholipid head groups; however, snorkelling's functional effects are obscure. Integrin β TMDs have such conserved basic amino acids. Here we use NMR spectroscopy to show that integrin β(3)(Lys 716) helps determine β(3) TMD topography. The α(ΙΙb)β(3) TMD structure indicates that precise β(3) TMD crossing angles enable the assembly of outer and inner membrane 'clasps' that hold the αβ TMD together to limit transmembrane signalling. Mutation of β(3)(Lys 716) caused dissociation of α(ΙΙb)β(3) TMDs and integrin activation. To confirm that altered topography of β(3)(Lys 716) mutants activated α(ΙΙb)β(3), we used directed evolution of β(3)(K716A) to identify substitutions restoring default state. Introduction of Pro(711) at the midpoint of β(3) TMD (A711P) increased α(ΙΙb)β(3) TMD association and inactivated integrin α(ΙΙb)β(3)(A711P,K716A). β(3)(Pro 711) introduced a TMD kink of 30 ± 1° precisely at the border of the outer and inner membrane clasps, thereby decoupling the tilt between these segments. Thus, widely occurring snorkelling residues in TMDs can help maintain TMD topography and membrane-embedding, thereby regulating transmembrane signalling. PMID:22178926
Influence of side-chain regiochemistry on the transistor performance of high-mobility, all-donor polymers.
Fei, Zhuping; Pattanasattayavong, Pichaya; Han, Yang; Schroeder, Bob C; Yan, Feng; Kline, R Joseph; Anthopoulos, Thomas D; Heeney, Martin
Three novel polythiophene isomers are reported whereby the only difference in structure relates to the regiochemistry of the solubilizing side chains on the backbone. This is demonstrated to have a significant impact on the optoelectronic properties of the polymers and their propensity to aggregate in solution. These differences are rationalized on the basis of differences in backbone torsion. The polymer with the largest effective conjugation length is demonstrated to exhibit the highest field-effect mobility, with peak values up to 4.6 cm(2) V(-1) s(-1). PMID:25302474
A method to configure protein side-chains from the main-chain trace in homology modelling.
Eisenmenger, F; Argos, P; Abagyan, R
Protein homology modelling typically involves the prediction of side-chain conformations in the modelled protein while assuming a main-chain trace taken from a known tertiary structure of a protein with homologous sequence. It is generally believed that the need to examine all possible combinations of side-chain conformations poses the major obstacle to accurate homology modelling. Methods proposed heretofore use only discrete or limited searches of the side-chain torsion angle space to mitigate the combinatorial problem and also rely on simplified energy functions for calculational speed. The configurational constraints are typically based upon use of frequently observed torsion angles, fixed steps in torsion angles, or oligopeptide segments taken from tertiary structural databanks that are similar in sequence and conformation with the target structure. In the present work, a more fundamental approach is explored for several protein structures and it is demonstrated that the combinatorial barrier in side-chain placement hardly exists. Each side-group can be configured individually in the environment of only the backbone atoms using a systematic search procedure combined with extensive local energy minimization. Tests, using the main-chain or both the main-chain and remaining side-chain atoms to calculate low energy geometries for each residue, established the dominance of the main-chain contribution. The final structure is achieved by combining the individually placed side-chains followed by a full energy refinement of the structure. The prediction accuracy of the present homology modelling technique was assessed relative to other automated procedures and was found to yield improved predictions relative to the known side-chain conformations determined by X-ray crystallography. PMID:8515455
Side chain directly participates in the solar absorption of fullerene derivative PC61BM
NASA Astrophysics Data System (ADS)
Xing, Xiu-Na; Chen, Guang-Hua; Du, Ying-Ying; Li, Wen-Jie; Li, Hai-Yang; Li, Hong-Nian; Li, Wei-Yin; Chen, Fu-Yi
We have studied the role of the phenyl-butyric-acid-methyl-ester side chain in the solar absorption of fullerene derivatives PC61BM. The UV-Vis-NIR spectra are calculated with the linear response theory within time-dependent density functional theory. The initial and final orbitals of the optical transitions in solar spectrum range are analyzed in detail. The electronic states of the side chain hybridize with the states of C60 cage, increasing the number of the initial orbitals of the solar absorption. So the side chain directly participates in the solar absorption. A distortion or length change of the side chain has obvious effects on the photoabsorption.
Switching effect of the side chain on quantum walks on triple graphs
NASA Astrophysics Data System (ADS)
Du, Yi-Mu; Lu, Li-Hua; Li, You-Quan
We consider a continuous-time quantum walk on a triple graph and investigate the influence of the side chain on propagation in the main chain. Calculating the interchange of the probabilities between the two parts of the main chain, we find that a switching effect appears if there is an odd number of points in the side chain when concrete conditions between the length of the main chain and the position of the side chain are satisfied. However, such an effect does not occur if there is an even number of points in the side chain. We also suggest two proposals for experiments to demonstrate this effect, which may be employed to design a new type of switching device.
Solvation thermodynamics of amino acid side chains on a short peptide backbone
Hajari, Timir; Vegt, Nico F. A. van der
The hydration process of side chain analogue molecules differs from that of the actual amino acid side chains in peptides and proteins owing to the effects of the peptide backbone on the aqueous solvent environment. A recent molecular simulation study has provided evidence that all nonpolar side chains, attached to a short peptide backbone, are considerably less hydrophobic than the free side chain analogue molecules. In contrast to this, the hydrophilicity of the polar side chains is hardly affected by the backbone. To analyze the origin of these observations, we here present a molecular simulation study on temperature dependent solvation free energies of nonpolar and polar side chains attached to a short peptide backbone. The estimated solvation entropies and enthalpies of the various amino acid side chains are compared with existing side chain analogue data. The solvation entropies and enthalpies of the polar side chains are negative, but in absolute magnitude smaller compared with the corresponding analogue data. The observed differences are large; however, owing to a nearly perfect enthalpy-entropy compensation, the solvation free energies of polar side chains remain largely unaffected by the peptide backbone. We find that a similar compensation does not apply to the nonpolar side chains; while the backbone greatly reduces the unfavorable solvation entropies, the solvation enthalpies are either more favorable or only marginally affected. This results in a very small unfavorable free energy cost, or even free energy gain, of solvating the nonpolar side chains in strong contrast to solvation of small hydrophobic or nonpolar molecules in bulk water. The solvation free energies of nonpolar side chains have been furthermore decomposed into a repulsive cavity formation contribution and an attractive dispersion free energy contribution. We find that cavity formation next to the peptide backbone is entropically favored over formation of similar sized nonpolar side
Macromolecular recognition: Recognition of polymer side chains by cyclodextrin
NASA Astrophysics Data System (ADS)
Hashidzume, Akihito; Harada, Akira
The interaction of cyclodextrins (CD) with water soluble polymers possessing guest residues has been investigated as model systems in biological molecular recognition. The selectivity of interaction of CD with polymer-carrying guest residues is controlled by polymer chains, i.e., the steric effect of polymer main chain, the conformational effect of polymer main chain, and multi-site interaction. Macroscopic assemblies have been also realized based on molecular recognition using polyacrylamide-based gels possessing CD and guest residues.
The Impact of Side-chain Packing on Protein Docking Refinement
Moghadasi, Mohammad; Mirzaei, Hanieh; Mamonov, Artem; Vakili, Pirooz; Vajda, Sandor; Paschalidis, Ioannis Ch.; Kozakov, Dima
We study the impact of optimizing side-chain positions in the interface region between two proteins during the process of binding. Mathematically, the problem is similar to side-chain prediction, extensively explored in the process of protein structure prediction. The protein-protein docking application, however, has a number of characteristics that necessitate different algorithmic and implementation choices. In this work, we implement a distributed approximate algorithm that can be implemented on multi-processor architectures and enables trading off accuracy with running speed. We report computational results on benchmarks of enzyme-inhibitor and other types of complexes, establishing that the side-chain flexibility our algorithm introduces substantially improves the performance of docking protocols. Further, we establish that the inclusion of unbound side-chain conformers in the side-chain positioning problem is critical in these performance improvements. PMID:25714358
Novel biaxial nematic phases of side-chain liquid crystalline polymers
NASA Astrophysics Data System (ADS)
Matsuyama, Akihiko
We present a mean field theory to describe biaxial nematic phases of side-chain liquid crystalline polymers, in which rigid side-chains (mesogens) and rigid-backbone chains favor mutually perpendicular orientations. Taking into account both excluded volume and attractive interactions between rigid rods, novel biaxial nematic phases are theoretically predicted. We calculate uniaxial and biaxial orientational order parameters as a function of temperature and the length of backbone chains. We find a first-order biaxial-biaxial phase transition and a first (or second)-order uniaxial-biaxial one, depending on the length of mesogens and backbone chains.
Effect of cationic side-chains on intracellular delivery and cytotoxicity of pH sensitive polymer-doxorubicin nanocarriers
NASA Astrophysics Data System (ADS)
Fang, Chen; Kievit, Forrest M.; Cho, Yong-Chan; Mok, Hyejung; Press, Oliver W.; Zhang, Miqin
Fine-tuning the design of polymer-doxorubicin conjugates permits optimization of an efficient nanocarrier to greatly increase intracellular uptake and cytotoxicity. Here, we report synthesis of a family of self-assembled polymer-doxorubicin nanoparticles and an evaluation of the effects of various types of side-chains on intracellular uptake and cytotoxicity of the nanocarriers for lymphoma cells. Monomers with three different cationic side-chains (CA) and pKa's, i.e., a guanidinium group (Ag), an imidazole group (Im), and a tertiary amine group (Dm), were comparatively investigated. The cationic monomer, poly(ethylene glycol) (PEG), and doxorubicin (Dox) were reacted with 1,4-(butanediol) diacrylate (BUDA) to prepare a poly(β-amino ester) (PBAE) polymer via Michael addition. All three polymer-Dox conjugates spontaneously formed nanoparticles (NP) through hydrophobic interactions between doxorubicin in aqueous solution, resulting in NP-Im/Dox, NP-Ag/Dox, and NP-Dm/Dox, with hydrodynamic sizes below 80 nm. Doxorubicin was linked to all 3 types of NPs with a hydrazone bond to assure selective release of doxorubicin only at acidic pH, as it occurs in the tumor microenvironment. Both NP-Im/Dox and NP-Ag/Dox exhibited much higher intracellular uptake by Ramos cells (Burkitt's lymphoma) than NP-Dm/Dox, suggesting that the type of side chain in the NPs determines the extent of intracellular uptake. As a result, NP-Im/Dox and NP-Ag/Dox showed cytotoxicity that was comparable to free Dox in vitro. Our findings suggest that the nature of surface cationic group on nanocarriers may profoundly influence their intracellular trafficking and resulting therapeutic efficacy. Thus, it is a crucial factor to be considered in the design of novel carriers for intracellular drug delivery.
On the effect of electron correlation on the static second hyperpolarizability of π conjugated oligomer chains.
Limacher, Peter A; Li, Qingxu; Lüthi, Hans P
In this article, we report on the ab initio calculation of the static longitudinal second hyperpolarizability (γ) of π conjugated unsaturated oligomer chains using polyacetylene and polyyne as model compounds. The common observation is that the electron correlation enhances γ in these systems. The present study reveals that for extended chain lengths the opposite appears to be true: Electron correlation may have a damping effect on this property. For double-zeta basis sets, a negative contribution from electron correlation to γ is found within the range of chain lengths investigated. For triple-zeta basis sets, the same behavior must be anticipated at larger chain lengths based on extrapolation schemes. The analysis of the excitation energies and transition moments shows that transition moments between excited states as predicted by the Hartree-Fock and coupled cluster methods have a different response to chain length extension. There also are indications that higher order correlation effects will enhance γ. PMID:21744892
Conformation and mobility of the arabinan and galactan side-chains of pectin.
Ha, Marie-Ann; Viëtor, Remco J; Jardine, Gordon D; Apperley, David C; Jarvis, Michael C
The function of the arabinan and galactan side-chains of pectin remains unknown. We describe 13C NMR experiments designed to yield spectra from the most mobile polymer components of hydrated cell walls isolated from a range of plant species. In pectin-rich cell walls, these corresponded to the pectic side-chains. The arabinan side-chains were in general more mobile than the galactans, but the long galactan side-chains of potato pectin showed high mobility. Due to motional line-narrowing effects these arabinan and galactan chains gave 13C NMR spectra of higher resolution than has previously been observed from 'solid' biopolymers. These spectra were similar to those reported for the arabinan and galactan polymers in the solution state, implying time-averaged conformations resembling those found in solution. The mobility of the highly esterified galacturonan in citrus cell walls overlapped with the lower end of the mobility range characteristic of the pectic side-chains. The cellulose-rich cell walls of flax phloem fibres gave spectra of low intensity corresponding to mobile type II arabinogalactans. Cell walls from oat coleoptiles appeared to contain no polymers as mobile as the pectic arabinans and galactans in primary cell walls of the other species examined. These properties of the pectic side-chains suggest a role in interacting with water. PMID:16019042
Cholesterol Analogs with Degradation-resistant Alkyl Side Chains Are Effective Mycobacterium tuberculosis Growth Inhibitors.
Frank, Daniel J; Zhao, Yan; Wong, Siew Hoon; Basudhar, Debashree; De Voss, James J; Ortiz de Montellano, Paul R
Cholest-4-en-3-one, whether added exogenously or generated intracellularly from cholesterol, inhibits the growth ofMycobacterium tuberculosiswhen CYP125A1 and CYP142A1, the cytochrome P450 enzymes that initiate degradation of the sterol side chain, are disabled. Here we demonstrate that a 16-hydroxy derivative of cholesterol, which was previously reported to inhibit growth ofM. tuberculosis, acts by preventing the oxidation of the sterol side chain even in the presence of the relevant cytochrome P450 enzymes. The finding that (25R)-cholest-5-en-3β,16β,26-triol (1) (and its 3-keto metabolite) inhibit growth suggests that cholesterol analogs with non-degradable side chains represent a novel class of anti-mycobacterial agents. In accord with this, two cholesterol analogs with truncated, fluorinated side chains have been synthesized and shown to similarly block the growth in culture ofM. tuberculosis. PMID:26833565
Excluded-volume interaction induced stiffness of comb polymer with densely grafted side-chains
NASA Astrophysics Data System (ADS)
Qiu, Feng
Excluded-volume interaction has been widely recognized to cause expansion of polymer chain at large length scale. However, its effect on chain conformations at small length scale has been studied to less extent. Here we consider a comb polymer with its backbone densely grafted by side-chains as a model system. The method analogue to solving the electrostatic persistence length problem for either rigid or flexible polyelectrolytes is employed. For comb polymers with rigid backbone near the rod limit, the excluded-volume interaction induced persistence length scales linearly with the volume of the side-chain. While for flexible backbone, the persistence length depends on the side-chain volume more weakly. Field theoretic method that is relevant to address this problem is also explored and discussed. Work supported by NSFC.
The Relaxation of Twisted Chiral Nematic Liquid Crystals with Side-Chain Polymeric Layer
NASA Astrophysics Data System (ADS)
Zhou, Xuan; Zhang, Zhidong
A generalized form of surface dissipation function, for the description of the relative motion of the nematic director with respect to the polymer side chains in twisted chiral nematic samples is proposed, and the relaxation time of such samples are investigated, using the perturbation analysis method proposed by Alexe-Ionescu et al. Our results show that the presence of both the surface dissipation and the polymer side chains increase the relaxation time.
Steroids with a side chain containing a heterocyclic fragment: synthesis and transformations
NASA Astrophysics Data System (ADS)
Baranovskii, Aleksander V.; Litvinovskaya, Raisa P.; Khripach, Vladimir A.
The latest data on the methods for the formation of the side chains of steroids containing a heterocyclic fragment are surveyed and described systematically. Attention is concentrated on the methods for the transformation of heterocycles in order to achieve the stereoselective formation of chiral centres in the side chain characteristic of a series of natural polyhydroxysteroids - ecdysones, brassinosteroids, vitamin D metabolites, etc. The bibliography includes 133 references.
Searching for low percolation thresholds within amphiphilic polymer membranes: The effect of side chain branching
NASA Astrophysics Data System (ADS)
Dorenbos, G.
Percolation thresholds for solvent diffusion within hydrated model polymeric membranes are derived from dissipative particle dynamics in combination with Monte Carlo (MC) tracer diffusion calculations. The polymer backbones are composed of hydrophobic A beads to which at regular intervals Y-shaped side chains are attached. Each side chain is composed of eight A beads and contains two identical branches that are each terminated with a pendant hydrophilic C bead. Four types of side chains are considered for which the two branches (each represented as [C], [AC], [AAC], or [AAAC]) are splitting off from the 8th, 6th, 4th, or 2nd A bead, respectively. Water diffusion through the phase separated water containing pore networks is deduced from MC tracer diffusion calculations. The percolation threshold for the architectures containing the [C] and [AC] branches is at a water volume fraction of ˜0.07 and 0.08, respectively. These are much lower than those derived earlier for linear architectures of various side chain length and side chain distributions. Control of side chain architecture is thus a very interesting design parameter to decrease the percolation threshold for solvent and proton transports within flexible amphiphilic polymer membranes.
Searching for low percolation thresholds within amphiphilic polymer membranes: The effect of side chain branching
Dorenbos, G.
Percolation thresholds for solvent diffusion within hydrated model polymeric membranes are derived from dissipative particle dynamics in combination with Monte Carlo (MC) tracer diffusion calculations. The polymer backbones are composed of hydrophobic A beads to which at regular intervals Y-shaped side chains are attached. Each side chain is composed of eight A beads and contains two identical branches that are each terminated with a pendant hydrophilic C bead. Four types of side chains are considered for which the two branches (each represented as [C], [AC], [AAC], or [AAAC]) are splitting off from the 8th, 6th, 4th, or 2nd A bead, respectively. Water diffusion through the phase separated water containing pore networks is deduced from MC tracer diffusion calculations. The percolation threshold for the architectures containing the [C] and [AC] branches is at a water volume fraction of ∼0.07 and 0.08, respectively. These are much lower than those derived earlier for linear architectures of various side chain length and side chain distributions. Control of side chain architecture is thus a very interesting design parameter to decrease the percolation threshold for solvent and proton transports within flexible amphiphilic polymer membranes.
A Markov Random Field Framework for Protein Side-Chain Resonance Assignment
NASA Astrophysics Data System (ADS)
Zeng, Jianyang; Zhou, Pei; Donald, Bruce Randall
Nuclear magnetic resonance (NMR) spectroscopy plays a critical role in structural genomics, and serves as a primary tool for determining protein structures, dynamics and interactions in physiologically-relevant solution conditions. The current speed of protein structure determination via NMR is limited by the lengthy time required in resonance assignment, which maps spectral peaks to specific atoms and residues in the primary sequence. Although numerous algorithms have been developed to address the backbone resonance assignment problem [68,2,10,37,14,64,1,31,60], little work has been done to automate side-chain resonance assignment [43, 48, 5]. Most previous attempts in assigning side-chain resonances depend on a set of NMR experiments that record through-bond interactions with side-chain protons for each residue. Unfortunately, these NMR experiments have low sensitivity and limited performance on large proteins, which makes it difficult to obtain enough side-chain resonance assignments. On the other hand, it is essential to obtain almost all of the side-chain resonance assignments as a prerequisite for high-resolution structure determination. To overcome this deficiency, we present a novel side-chain resonance assignment algorithm based on alternative NMR experiments measuring through-space interactions between protons in the protein, which also provide crucial distance restraints and are normally required in high-resolution structure determination. We cast the side-chain resonance assignment problem into a Markov Random Field (MRF) framework, and extend and apply combinatorial protein design algorithms to compute the optimal solution that best interprets the NMR data. Our MRF framework captures the contact map information of the protein derived from NMR spectra, and exploits the structural information available from the backbone conformations determined by orientational restraints and a set of discretized side-chain conformations (i.e., rotamers). A Hausdorff
Peptide Nucleic Acid with a Lysine Side Chain at the β-Position: Synthesis and Application for DNA Cleavage.
Sugiyama, Toru; Kuwata, Keiko; Imamura, Yasutada; Demizu, Yosuke; Kurihara, Masaaki; Takano, Masashi; Kittaka, Atsushi
This paper reports the synthesis of new β-Lys peptide nucleic acid (PNA) monomers and their incorporation into a 10-residue PNA sequence. PNA containing β-Lys PNA units formed a stable hybrid duplex with DNA. However, incorporation of β-Lys PNA units caused destabilization of PNA-DNA duplexes to some extent. Electrostatic attractions between β-PNA and DNA could reduce this destabilization effect. Subsequently, bipyridine-conjugated β-Lys PNA was prepared and exhibited sequence selective cleavage of DNA. Based on the structures of the cleavage products and molecular modeling, we reasoned that bipyridine moiety locates within the minor groove of the PNA-DNA duplexes. The lysine side chain of β-PNA is a versatile handle for attaching various functional molecules. PMID:27373637
Linear rheology and structure of molecular bottlebrushes with short side chains
López-Barrón, Carlos R. Brant, Patrick; Crowther, Donna J.; Eberle, Aaron P. R.
We investigate the microstructure and linear viscoelasticity of model molecular bottlebrushes (BBs) using rheological and small-angle X-ray and neutron scattering measurements. Our polymers have short atactic polypropylene (aPP) side chains of molecular weight ranging from 119 g/mol to 259 g/mol and narrow molecular weight distribution (M{sub w}/M{sub n} 1.02–1.05). The side chain molecular weights are a small fraction of the entanglement molecular weight of the corresponding linear polymer (M{sub e,aPP}= 7.05 kg/mol), and as such, they are unentangled. The morphology of the aPP BBs is characterized as semiflexible thick chains with small side chain interdigitation. Their dynamic master curves, obtained by time-temperature superposition, reveal two sequential relaxation processes corresponding to the segmental relaxation and the relaxation of the BB backbone. Due to the short length of the side chains, their fast relaxation could not be distinguished from the glassy relaxation. The fractional free volume is an increasing function of the side chain length (N{sub SC}). Therefore, the glassy behavior of these polymers as well as their molecular friction and dynamic properties are influenced by their N{sub SC} values. The apparent flow activation energies are a decreasing function of N{sub SC}, and their values explain the differences in zero-shear viscosity measured at different temperatures.
Z-Group ketone chain transfer agents for RAFT polymer nanoparticle modification via hydrazone conjugation
Bandyopadhyay, Saibal; Xia, Xin; Maiseiyeu, Andrei; Mihai, Georgeta; Rajagopalan, Sanjay
A ketal-containing trithiocarbonyl compound has been synthesized and characterized as a chain transfer agent (CTA) in Reversible Addition Fragmentation Transfer (RAFT) polymerization. The ketal functionality does not interfere with RAFT polymerization of acrylate monomers, which proceeds as previously reported to yield macro-CTA polymers and block co-polymers. Post-polymerization ketal cleavage revealed ketone functionality at the polar terminus of an amphiphilic block co-polymer. Hydrazone-formation was facile in both organic solution as well as in aqueous buffer where polymer nanoparticle assemblies were formed, indicating a conjugation/end-functionalization yield of 40–50%. Conjugation was verified with fluorescein, biotin and Gd-DOTA derivatives, and though the trithiocarbonate linkage is hydrolytically labile, we observed stable conjugation for several days at pH 7.4. and 37°C. As expected, streptavidin binding to biotinylated polymer micelles was observed, and size-change based relaxivity increases were observed when Gd-DOTA hydrazide was conjugated to polymer micelles. Cell-uptake of fluorescently labeled polymer micelles was also readily tracked by FACS and fluorescence microscopy. These polymer derivatives demonstrate a range of potential theranostic/biotechnological applications for this conveniently accessible keto-CTA, which include ligand-based nanoparticle targeting and fluorescent/MR nanoparticle contrast agents. PMID:23148126
Star-Shaped Conjugated Molecules with Oxa- or Thiadiazole Bithiophene Side Arms.
Kotwica, Kamil; Kostyuchenko, Anastasia S; Data, Przemyslaw; Marszalek, Tomasz; Skorka, Lukasz; Jaroch, Tomasz; Kacka, Sylwia; Zagorska, Malgorzata; Nowakowski, Robert; Monkman, Andrew P; Fisyuk, Alexander S; Pisula, Wojciech; Pron, Adam
Star-shaped conjugated molecules, consisting of a benzene central unit symmetrically trisubstituted with either oxa- or thiadiazole bithiophene groups, were synthesized as promising molecules and building blocks for application in (opto)electronics and electrochromic devices. Their optical (Eg (opt)) as well as electrochemical (Eg (electro)) band gaps depended on the type of the side arm and the number of solubilizing alkyl substituents. Oxadiazole derivatives showed Eg (opt) slightly below 3 eV and by 0.2 eV larger than those determined for thiadiazole-based compounds. The presence of alkyl substituents in the arms additionally lowered the band gap. The obtained compounds were efficient electroluminophores in guest/host-type light-emitting diodes. They also showed a strong tendency to self-organize in monolayers deposited on graphite, as evidenced by scanning tunneling microscopy. The structural studies by X-ray scattering revealed the formation of supramolecular columnar stacks in which the molecules were organized. Differences in macroscopic alignment in the specimen indicated variations in the self-assembly mechanism between the molecules. The compounds as trifunctional monomers were electrochemically polymerized to yield the corresponding polymer network. As shown by UV/Vis-NIR spectroelectrochemical studies, these networks exhibited reversible electrochromic behavior both in the oxidation and in the reduction modes. PMID:27404332
SDRL: a sequence-dependent protein side-chain rotamer library.
Taghizadeh, Mohammad; Goliaei, Bahram; Madadkar-Sobhani, Armin
Since the introduction of the first protein side-chain rotamer library (RL) almost half a century ago, RLs have been components of many programs and algorithms in structural bioinformatics. Based on the dependence of side-chain dihedral angles on the local backbone, three types of RLs have been identified: backbone-independent, secondary-structure-dependent and backbone-dependent. In all previous studies, the effect of sequence specificity on side-chain conformational preferences was neglected. In the effort to develop a new class of RLs, we considered that the side-chain conformation of the central residue in each triplet on a protein backbone depends on the sequence of the triplet; therefore, we developed a sequence-dependent rotamer library (SDRL). To accomplish this, 400 possible triplet sequences for 18 natural amino acids as the central residue, which corresponds to 7200 triplet sequences in total, were considered. Searching the set of 11 546 selected PDB entries for the 7200 triplet sequences resulted in 2 364 541 instances occurring for 18 amino acids. Our results show that Leu and Val experience minimal impact from the adjacent residues in adopting side-chain conformations. Cys, Ile, Trp, His, Asp, Met, Glu, Gln, Arg and Lys, on the other hand, adopt their side-chain conformations mostly based on the adjacent residues on the backbone. The remaining residue types were moderately dependent on the adjacent residues. Using the new library, side-chain repacking algorithms can find preferred conformations of each residue more easily than with other backbone-independent RLs. PMID:25953624
UV resonance Raman and DFT studies of arginine side chains in peptides: insights into arginine hydration.
Hong, Zhenmin; Wert, Jonathan; Asher, Sanford A
We examined the UV resonance Raman (UVRR) spectra of four models of the Arg side chain, guanidinium (Gdn), ethylguanidinium (EG), arginine (Arg), and Ac-Arg-OMe (AAO) in H2O and D2O, in order to identify spectral markers that report on the environment of the Arg side chain. To elucidate the resonance Raman enhancement mechanism of the Arg side chain, we used density functional theory (DFT) to calculate the equilibrium geometries of the electronic ground state and the first excited state. We determined the vibrational mode frequencies of the ground state and the first derivative of the first electronic excited state potential energy with respect to each vibrational normal mode of the electronic ground state at the electronic ground state equilibrium geometry. The DFT calculations and the potential energy distributions reveal that, in addition to the Gdn group C-N stretching vibrations, the C-N bond stretching vibration of the Gdn group-methylene linkage is also strongly resonance-enhanced in EG, Arg, and AAO. From the UVRR spectra, we find that the Raman cross section and frequency of the ~1170 cm(-1) vibration of the Arg side chain depends on its hydration state and can be used to determine the hydration state of the Arg side chain in peptides and proteins. We examined the hydration of the Arg side chain in two polyAla peptides and found that in the α-helical conformation the Arg side chain in the AEP peptide (sequence: A9RA3EA4RA2) is less hydrated than that in the AP peptide (sequence: A8RA4RA4RA2). PMID:23676082
UV Resonance Raman and DFT Studies of Arginine Side Chains in Peptides: Insights into Arginine Hydration
Hong, Zhenmin; Wert, Jonathan; Asher, Sanford A.
We examined the UV resonance Raman (UVRR) spectra of four models of the arg side chain, guanidinium (gdn), ethylguanidinium (EG), arginine (arg) and Ac-arg-OMe (AAO) in H2O and D2O, in order to identify spectral markers that report on the environment of the arg side chain. To elucidate the resonance Raman enhancement mechanism of the arg side chain, we used DFT to calculate the equilibrium geometries of the electronic ground state and the first excited state. We determined the vibrational mode frequencies of the ground state and the first derivative of the first electronic excited state potential energy with respect to each vibrational normal mode of the electronic ground state at the electronic ground state equilibrium geometry. The DFT calculations and the potential energy distributions reveal that, in addition to the gdn group C-N stretching vibrations, the C-N bond stretching vibration of the gdn group-methylene linkage is also strongly resonance enhanced in EG, arg and AAO. From the UVRR spectra, we find that the Raman cross section and frequency of the ~1170 cm−1 vibration of the arg side chain depends on its hydration state and can be used to determine the hydration state of the arg side chain in peptides and proteins. We examined the hydration of the arg side chain in two polyala peptides and found that in the α-helical conformation the arg side chain in the AEP peptide (sequence: A9RA3EA4RA2) is less hydrated than that in the AP peptide (sequence: A8RA4RA4RA2). PMID:23676082
Side Chain Engineering of Naphthalenediimide-Based N-type Polymer for High-Performance All-Polymer Solar Cell near 6% Efficiency
NASA Astrophysics Data System (ADS)
Lee, Changyeon; Kang, Hyunbum; Lee, Wonho; Kim, Taesu; Kim, Ki-Hyun; Woo, Han Young; Wang, Cheng; Kim, Bumjoon; Pusan National University (PNU) Collaboration; Lawrence Berkeley National Laboratory Collaboration
Despite the attractive features of all-polymer solar cells (all-PSCs), i.e., enhanced absorption coefficients, the tunability of their energetic and chemical properties and their thermal and mechanical stabilities, they still face the great challenge of having significantly low power conversion efficiency (PCE) values of only 3-5%. The prominent origins of the poor efficiency of all-PSCs are the undesirable features of the bulk-heterojunction (BHJ) blend morphology including the phase-separated large-scale domain size, reduced ordering of the polymer chains. Tuning side alkyl chains of conjugated polymers is an effective route for manipulating the blend morphology in BHJ type solar cells. However, the role of side chains in all-PSCs is poorly understood. Herein, we report high-performing all-PSCs with 5.96% efficiency by developing a series of naphthalenediimide (NDI)-based polymer acceptors with different alkyl side chains. We demonstrated that the use of the PNDIT with hexyldecyl side chains produced highly-ordered polymer stackings with strong face-on geometry and at the same time, forming the optimal BHJ morphology with finely separated phase domains, all of which contributed together to induce well-balanced μe/ μh ratio and generate efficient all-PSCs with PCEs near 6%.
Assessment of Protein Side-Chain Conformation Prediction Methods in Different Residue Environments
Peterson, Lenna X.; Kang, Xuejiao; Kihara, Daisuke
Computational prediction of side-chain conformation is an important component of protein structure prediction. Accurate side-chain prediction is crucial for practical applications of protein structure models that need atomic detailed resolution such as protein and ligand design. We evaluated the accuracy of eight side-chain prediction methods in reproducing the side-chain conformations of experimentally solved structures deposited to the Protein Data Bank. Prediction accuracy was evaluated for a total of four different structural environments (buried, surface, interface, and membrane-spanning) in three different protein types (monomeric, multimeric, and membrane). Overall, the highest accuracy was observed for buried residues in monomeric and multimeric proteins. Notably, side-chains at protein interfaces and membrane-spanning regions were better predicted than surface residues even though the methods did not all use multimeric and membrane proteins for training. Thus, we conclude that the current methods are as practically useful for modeling protein docking interfaces and membrane-spanning regions as for modeling monomers. PMID:24619909
From isotropic to anisotropic side chain representations: comparison of three models for residue contact estimation.
Sun, Weitao; He, Jing
The criterion to determine residue contact is a fundamental problem in deriving knowledge-based mean-force potential energy calculations for protein structures. A frequently used criterion is to require the side chain center-to-center distance or the -to- atom distance to be within a pre-determined cutoff distance. However, the spatially anisotropic nature of the side chain determines that it is challenging to identify the contact pairs. This study compares three side chain contact models: the Atom Distance criteria (ADC) model, the Isotropic Sphere Side chain (ISS) model and the Anisotropic Ellipsoid Side chain (AES) model using 424 high resolution protein structures in the Protein Data Bank. The results indicate that the ADC model is the most accurate and ISS is the worst. The AES model eliminates about 95% of the incorrectly counted contact-pairs in the ISS model. Algorithm analysis shows that AES model is the most computational intensive while ADC model has moderate computational cost. We derived a dataset of the mis-estimated contact pairs by AES model. The most misjudged pairs are Arg-Glu, Arg-Asp and Arg-Tyr. Such a dataset can be useful for developing the improved AES model by incorporating the pair-specific information for the cutoff distance. PMID:21552527
Computational Investigation of the Photochemical Reaction Path of Some Synthesized and Experimentally Analyzed Small-Chain Conjugated Nitrones.
Saini, Praveen; Banerjee, Mainak; Chattopadhyay, Anjan
This combined theoretical and experimental study has revealed the photochemistry of two small open-chain conjugated N-methylnitrone systems with phenyl substitutions at the C-terminal positions. The UV spectra of these synthesized nitrones have shown intense peaks around 330 nm while the new bands formed near 260 nm after their photoirradiation are predicted to be arising from the photoproduct oxaziridine. Photoexcitation of α-styryl N-methylnitrone populates the first excited singlet state which relaxes by 8 kcal/mol from the vertically excited state and subsequently goes toward the lowest-energy conical intersection (CI) geometry (situated 27-30 kcal/mol below) with a terminal CNO-kink. Following the gradient difference vectors of this CI, we have located the oxaziridine structure with its characteristic geometry at roughly 14 kcal/mol above the ground state. This whole process is triggered by a transfer of electronic cloud from oxygen to the conjugated chain side. On the other hand, the photoexcitation of the nonplanar 3,3-diphenylethylene N-methylnitrone has two strong singlet-singlet absorptions with almost 5 D transition moment values. Here the initial S2-S1 relaxation is followed by oxaziridine formation through the terminally twisted CI. However, the initially photoexcited S1 state in this nitrone is found to head toward some other direction with transfer of huge amount of nonbonding electron cloud of oxygen to the π* orbital, creating a stable excited state geometry with an elongated N-O bond which gets involved in a sloped CI with the ground state. PMID:26697926
Property peculiarities of the atelocollagen-hyaluronan conjugates crosslinked with a short chain di-oxirane compound.
Maier, Vasilica; Lefter, Cristina M; Maier, Stelian S; Butnaru, Maria; Danu, Maricel; Ibanescu, Constanta; Popa, Marcel; Desbrieres, Jacques
Minimal amounts of a short-chain bifunctional crosslinker of about 1.3 nm length, the 1,4-butanediol-diglycidyl ether (BDDGE), were used to generate atelocollagen-hyaluronan conjugates in hydrogel state. Two a priori constraints were considered in recipe/procedure developing: (i) working in nondenaturing conditions, and (ii) ensuring a low cytotoxicity of the final product. Both atelocollagen (aK) and hyaluronan (NaHyal) were accurately purified to reduce their molecular-weight dispersity, in order to ensure the reproducibility of hydrogels characteristics. 1:5 aK:NaHyal weight ratios and 1:2.5 to 1:5 α-NH2:BDDGE molar ratios were found to be the most favorable recipe prescriptions that allow the obtaining of rheo-mechanically stable hydrogels, able to be manipulated during cell culturing protocols. Experiments revealed two unexpected effects due to the crosslinking reactions mediated by a short-chain molecule: (i) the occurrence of two thresholds in the rheological behavior of the hydrogels, related with the amount of added crosslinker, and (ii) a quasi-denaturation side-effect induced over the protein component by large or in excess amounts of crosslinker. PMID:25063116
Influence of side chains on the self-alignment capability of electroluminescent polyfluorenes.
Lee, Sunyoung; Yang, Yooseong; Kwon, Sunchul; Jung, Youngsuk
We report a significant role of side chains in the propagation of molecular orientation upon annealing the liquid crystal phase of polyfluorenes. Direct rubbing of poly(9,9-di(octyl)fluorene) led to the orientation of polymer segments in the top-most region of the film and enhanced propagation of this orientation along the rubbing direction was observed upon annealing. In contrast, the rubbing-induced molecular orientation of poly(9,9-di(ethylhexyl)fluorene) segments completely disappeared upon annealing in the nematic melt state. The higher order of the side chain structures in poly(9,9-di(octyl)fluorene) were found to allow the propagation of the three-dimensional molecular alignment. From integrated experimental and density functional theory studies, we propose that side chain interdigitation generates a unique alignment behavior of poly(9,9-di(octyl)fluorene). PMID:26743162
Bottlebrush Copolymer Morphology Transition: Influence of Side Chain Length and Block Volume Fraction
NASA Astrophysics Data System (ADS)
Gai, Yue; Song, Dong-Po; Watkins, James
Brush block copolymers synthesized via living ring-opening metathesis polymerization (ROMP) offer unique advantages as templates for functional hybrid materials. Unlike linear block copolymer, the bottlebrush polymer phase transition not only depends on volume fractions of the two blocks but also on side chain length. Here we report the morphology transitions of PS-b-PEO bottlebrush copolymer (BBCP) as a function of PEO side chain length and block volume fraction. For the BBCPs with similar side chain lengths, highly ordered lamellar morphologies were observed with PEO volume fractions in a wide range from 32 vol% to 72 vol%, which is significantly different from that of traditional linear block copolymers. This study will lay the groundwork for nanostructure fabrications using the BBCPs and provides new insights into the phase behavior of the new type of materials. This work was supported by NSF center for Hierarchical Manufacturing at the University of Massachusetts, Amherst.
Pyrrolidinobenzoic Acid Inhibitors of Influenza Virus Neuraminidase: the Hydrophobic Side Chain Influences Type A Subtype Selectivity
Li, Yanwu; Silamkoti, Arundutt; Kolavi, Gundurao; Mou, Liyuan; Gulati, Shelly; Air, Gillian M.
Neuraminidase (NA) plays a critical role in the life cycle of influenza virus and is a target for new therapeutic agents. A series of influenza neuraminidase inhibitors with the pyrrolidinobenzoic acid scaffold containing lipophilic side chains at the C3 position have been synthesized and evaluated for influenza neuraminidase inhibitory activity. The size and geometry of the C3 side chains have been modified in order to investigate structure-activity relationships. The results indicated that size and geometry of the C3-side chain are important for selectivity of inhibition against N1 vs N2 NA, important type A influenza variants that infect man, including the highly lethal avian influenza. PMID:22677529
Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: the hydrophobic side chain influences type A subtype selectivity.
Li, Yanwu; Silamkoti, Arundutt; Kolavi, Gundurao; Mou, Liyuan; Gulati, Shelly; Air, Gillian M; Brouillette, Wayne J
Neuraminidase (NA) plays a critical role in the life cycle of influenza virus and is a target for new therapeutic agents. A series of influenza neuraminidase inhibitors with the pyrrolidinobenzoic acid scaffold containing lipophilic side chains at the C3 position have been synthesized and evaluated for influenza neuraminidase inhibitory activity. The size and geometry of the C3 side chains have been modified in order to investigate structure-activity relationships. The results indicated that size and geometry of the C3-side chain are important for selectivity of inhibition against N1 versus N2 NA, important type A influenza variants that infect man, including the highly lethal avian influenza. PMID:22677529
Record high hole mobility in polymer semiconductors via side-chain engineering.
Kang, Il; Yun, Hui-Jun; Chung, Dae Sung; Kwon, Soon-Ki; Kim, Yun-Hi
Charge carrier mobility is still the most challenging issue that should be overcome to realize everyday organic electronics in the near future. In this Communication, we show that introducing smart side-chain engineering to polymer semiconductors can facilitate intermolecular electronic communication. Two new polymers, P-29-DPPDBTE and P-29-DPPDTSE, which consist of a highly conductive diketopyrrolopyrrole backbone and an extended branching-position-adjusted side chain, showed unprecedented record high hole mobility of 12 cm(2)/(V·s). From photophysical and structural studies, we found that moving the branching position of the side chain away from the backbone of these polymers resulted in increased intermolecular interactions with extremely short π-π stacking distances, without compromising solubility of the polymers. As a result, high hole mobility could be achieved even in devices fabricated using the polymers at room temperature. PMID:24053786
Equilibrium transitions between side-chain conformations in leucine and isoleucine.
Caballero, Diego; Smith, W Wendell; O'Hern, Corey S; Regan, Lynne
Despite recent improvements in computational methods for protein design, we still lack a quantitative, predictive understanding of the intrinsic probabilities for amino acids to adopt particular side-chain conformations. Surprisingly, this question has remained unsettled for many years, in part because of inconsistent results from different experimental approaches. To explicitly determine the relative populations of different side-chain dihedral angles, we performed all-atom hard-sphere Langevin Dynamics simulations of leucine (Leu) and isoleucine (Ile) dipeptide mimetics with stereo-chemical constraints and repulsive-only steric interactions between non-bonded atoms. We determine the relative populations of the different χ(1) and χ(2) dihedral angle combinations as a function of the backbone dihedral angles ϕ and ψ. We also propose, and test, a mechanism for inter-conversion between the different side-chain conformations. Specifically, we discover that some of the transitions between side-chain dihedral angle combinations are very frequent, whereas others are orders of magnitude less frequent, because they require rare coordinated motions to avoid steric clashes. For example, to transition between different values of χ(2), the Leu side-chain bond angles κ(1) and κ(2) must increase, whereas to transition in χ(1), the Ile bond angles λ(1) and λ(2) must increase. These results emphasize the importance of computational approaches in stimulating further experimental studies of the conformations of side-chains in proteins. Moreover, our studies emphasize the power of simple steric models to inform our understanding of protein structure, dynamics, and design. PMID:26018846
Naphthalene Tetracarboxydiimide-Based n-Type Polymers with Removable Solubility via Thermally Cleavable Side Chains.
Hillebrandt, Sabina; Adermann, Torben; Alt, Milan; Schinke, Janusz; Glaser, Tobias; Mankel, Eric; Hernandez-Sosa, Gerardo; Jaegermann, Wolfram; Lemmer, Uli; Pucci, Annemarie; Kowalsky, Wolfgang; Müllen, Klaus; Lovrincic, Robert; Hamburger, Manuel
Multilayer solution-processed devices in organic electronics show the tendency of intermixing of subsequently deposited layers. Here, we synthesize naphthalene tetracarboxydiimide (NDI)-based n-type semiconducting polymers with thermally cleavable side chains which upon removal render the polymer insoluble. Infrared and photoelectron spectroscopy were performed to investigate the pyrolysis process. Characterization of organic field-effect transistors provides insight into charge transport. After the pyrolysis homogeneous films could be produced which are insoluble in the primary solvent. By varying curing temperature and time we show that these process parameters govern the amount of side chains in the film and influence the device performance. PMID:26829619
BetaSCPWeb: side-chain prediction for protein structures using Voronoi diagrams and geometry prioritization.
Ryu, Joonghyun; Lee, Mokwon; Cha, Jehyun; Laskowski, Roman A; Ryu, Seong Eon; Kim, Deok-Soo
Many applications, such as protein design, homology modeling, flexible docking, etc. require the prediction of a protein's optimal side-chain conformations from just its amino acid sequence and backbone structure. Side-chain prediction (SCP) is an NP-hard energy minimization problem. Here, we present BetaSCPWeb which efficiently computes a conformation close to optimal using a geometry-prioritization method based on the Voronoi diagram of spherical atoms. Its outputs are visual, textual and PDB file format. The web server is free and open to all users at http://voronoi.hanyang.ac.kr/betascpweb with no login requirement. PMID:27151195
Covalent docking using autodock: Two-point attractor and flexible side chain methods.
Bianco, Giulia; Forli, Stefano; Goodsell, David S; Olson, Arthur J
We describe two methods of automated covalent docking using Autodock4: the two-point attractor method and the flexible side chain method. Both methods were applied to a training set of 20 diverse protein-ligand covalent complexes, evaluating their reliability in predicting the crystallographic pose of the ligands. The flexible side chain method performed best, recovering the pose in 75% of cases, with failures for the largest inhibitors tested. Both methods are freely available at the AutoDock website (http://autodock.scripps.edu). PMID:26103917
BetaSCPWeb: side-chain prediction for protein structures using Voronoi diagrams and geometry prioritization
Ryu, Joonghyun; Lee, Mokwon; Cha, Jehyun; Laskowski, Roman A.; Ryu, Seong Eon; Kim, Deok-Soo
Many applications, such as protein design, homology modeling, flexible docking, etc. require the prediction of a protein's optimal side-chain conformations from just its amino acid sequence and backbone structure. Side-chain prediction (SCP) is an NP-hard energy minimization problem. Here, we present BetaSCPWeb which efficiently computes a conformation close to optimal using a geometry-prioritization method based on the Voronoi diagram of spherical atoms. Its outputs are visual, textual and PDB file format. The web server is free and open to all users at http://voronoi.hanyang.ac.kr/betascpweb with no login requirement. PMID:27151195
Side-chain Engineering of Benzo[1,2-b:4,5-b']dithiophene Core-structured Small Molecules for High-Performance Organic Solar Cells
NASA Astrophysics Data System (ADS)
Yin, Xinxing; An, Qiaoshi; Yu, Jiangsheng; Guo, Fengning; Geng, Yongliang; Bian, Linyi; Xu, Zhongsheng; Zhou, Baojing; Xie, Linghai; Zhang, Fujun; Tang, Weihua
Three novel small molecules have been developed by side-chain engineering on benzo[1,2-b:4,5-b']dithiophene (BDT) core. The typical acceptor-donor-acceptor (A-D-A) structure is adopted with 4,8-functionalized BDT moieties as core, dioctylterthiophene as π bridge and 3-ethylrhodanine as electron-withdrawing end group. Side-chain engineering on BDT core exhibits small but measurable effect on the optoelectronic properties of small molecules. Theoretical simulation and X-ray diffraction study reveal the subtle tuning of interchain distance between conjugated backbones has large effect on the charge transport and thus the photovoltaic performance of these molecules. Bulk-heterojunction solar cells fabricated with a configuration of ITO/PEDOT:PSS/SM:PC71BM/PFN/Al exhibit a highest power conversion efficiency (PCE) of 6.99% after solvent vapor annealing.
Side-chain Engineering of Benzo[1,2-b:4,5-b']dithiophene Core-structured Small Molecules for High-Performance Organic Solar Cells
Yin, Xinxing; An, Qiaoshi; Yu, Jiangsheng; Guo, Fengning; Geng, Yongliang; Bian, Linyi; Xu, Zhongsheng; Zhou, Baojing; Xie, Linghai; Zhang, Fujun; Tang, Weihua
Three novel small molecules have been developed by side-chain engineering on benzo[1,2-b:4,5-b']dithiophene (BDT) core. The typical acceptor-donor-acceptor (A-D-A) structure is adopted with 4,8-functionalized BDT moieties as core, dioctylterthiophene as π bridge and 3-ethylrhodanine as electron-withdrawing end group. Side-chain engineering on BDT core exhibits small but measurable effect on the optoelectronic properties of small molecules. Theoretical simulation and X-ray diffraction study reveal the subtle tuning of interchain distance between conjugated backbones has large effect on the charge transport and thus the photovoltaic performance of these molecules. Bulk-heterojunction solar cells fabricated with a configuration of ITO/PEDOT:PSS/SM:PC71BM/PFN/Al exhibit a highest power conversion efficiency (PCE) of 6.99% after solvent vapor annealing. PMID:27140224
Side-chain Engineering of Benzo[1,2-b:4,5-b']dithiophene Core-structured Small Molecules for High-Performance Organic Solar Cells.
Yin, Xinxing; An, Qiaoshi; Yu, Jiangsheng; Guo, Fengning; Geng, Yongliang; Bian, Linyi; Xu, Zhongsheng; Zhou, Baojing; Xie, Linghai; Zhang, Fujun; Tang, Weihua
Three novel small molecules have been developed by side-chain engineering on benzo[1,2-b:4,5-b']dithiophene (BDT) core. The typical acceptor-donor-acceptor (A-D-A) structure is adopted with 4,8-functionalized BDT moieties as core, dioctylterthiophene as π bridge and 3-ethylrhodanine as electron-withdrawing end group. Side-chain engineering on BDT core exhibits small but measurable effect on the optoelectronic properties of small molecules. Theoretical simulation and X-ray diffraction study reveal the subtle tuning of interchain distance between conjugated backbones has large effect on the charge transport and thus the photovoltaic performance of these molecules. Bulk-heterojunction solar cells fabricated with a configuration of ITO/PEDOT:PSS/SM:PC71BM/PFN/Al exhibit a highest power conversion efficiency (PCE) of 6.99% after solvent vapor annealing. PMID:27140224
Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis.
Marous, Daniel R; Lloyd, Evan P; Buller, Andrew R; Moshos, Kristos A; Grove, Tyler L; Blaszczyk, Anthony J; Booker, Squire J; Townsend, Craig A
Despite their broad anti-infective utility, the biosynthesis of the paradigm carbapenem antibiotic, thienamycin, remains largely unknown. Apart from the first two steps shared with a simple carbapenem, the pathway sharply diverges to the more structurally complex members of this class of β-lactam antibiotics, such as thienamycin. Existing evidence points to three putative cobalamin-dependent radical S-adenosylmethionine (RS) enzymes, ThnK, ThnL, and ThnP, as potentially being responsible for assembly of the ethyl side chain at C6, bridgehead epimerization at C5, installation of the C2-thioether side chain, and C2/3 desaturation. The C2 substituent has been demonstrated to be derived by stepwise truncation of CoA, but the timing of these events with respect to C2-S bond formation is not known. We show that ThnK of the three apparent cobalamin-dependent RS enzymes performs sequential methylations to build out the C6-ethyl side chain in a stereocontrolled manner. This enzymatic reaction was found to produce expected RS methylase coproducts S-adenosylhomocysteine and 5'-deoxyadenosine, and to require cobalamin. For double methylation to occur, the carbapenam substrate must bear a CoA-derived C2-thioether side chain, implying the activity of a previous sulfur insertion by an as-yet unidentified enzyme. These insights allow refinement of the central steps in complex carbapenem biosynthesis. PMID:26240322
Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis
Marous, Daniel R.; Lloyd, Evan P.; Buller, Andrew R.; Moshos, Kristos A.; Grove, Tyler L.; Blaszczyk, Anthony J.; Booker, Squire J.; Townsend, Craig A.
Despite their broad anti-infective utility, the biosynthesis of the paradigm carbapenem antibiotic, thienamycin, remains largely unknown. Apart from the first two steps shared with a simple carbapenem, the pathway sharply diverges to the more structurally complex members of this class of β-lactam antibiotics, such as thienamycin. Existing evidence points to three putative cobalamin-dependent radical S-adenosylmethionine (RS) enzymes, ThnK, ThnL, and ThnP, as potentially being responsible for assembly of the ethyl side chain at C6, bridgehead epimerization at C5, installation of the C2-thioether side chain, and C2/3 desaturation. The C2 substituent has been demonstrated to be derived by stepwise truncation of CoA, but the timing of these events with respect to C2–S bond formation is not known. We show that ThnK of the three apparent cobalamin-dependent RS enzymes performs sequential methylations to build out the C6-ethyl side chain in a stereocontrolled manner. This enzymatic reaction was found to produce expected RS methylase coproducts S-adenosylhomocysteine and 5′-deoxyadenosine, and to require cobalamin. For double methylation to occur, the carbapenam substrate must bear a CoA-derived C2-thioether side chain, implying the activity of a previous sulfur insertion by an as-yet unidentified enzyme. These insights allow refinement of the central steps in complex carbapenem biosynthesis. PMID:26240322
Structure and dynamics of an imidazoline nitroxide side chain with strongly hindered internal motion in proteins
NASA Astrophysics Data System (ADS)
Toledo Warshaviak, Dora; Khramtsov, Valery V.; Cascio, Duilio; Altenbach, Christian; Hubbell, Wayne L.
A disulfide-linked imidazoline nitroxide side chain (V1) has a similar and highly constrained internal motion at diverse topological sites in a protein, unlike that for the disulfide-linked pyrroline nitroxide side chain (R1) widely used in site directed spin labeling EPR. Crystal structures of V1 at two positions in a helix of T4 Lysozyme and quantum mechanical calculations suggest the source of the constraints as intra-side chain interactions of the disulfide sulfur atoms with both the protein backbone and the 3-nitrogen in the imidazoline ring. These interactions apparently limit the conformation of the side chain to one of only three possible rotamers, two of which are observed in the crystal structure. An inter-spin distance measurement in frozen solution using double electron-electron resonance (DEER) gives a value essentially identical to that determined from the crystal structure of the protein containing two copies of V1, indicating that lattice forces do not dictate the rotamers observed. Collectively, the results suggest the possibility of predetermining a unique rotamer of V1 in helical structures. In general, the reduced rotameric space of V1 compared to R1 should simplify interpretation of inter-spin distance information in terms of protein structure, while the highly constrained internal motion is expected to extend the dynamic range for characterizing large amplitude nanosecond backbone fluctuations.
Arabidopsis GUX Proteins Are Glucuronyltransferases Responsible for the Addition of Glucuronic Acid Side Chains onto Xylan
Xylan, the second most abundant cell wall polysaccharide, is composed of a linear backbone of β-(1,4)-linked xylosyl residues that are often substituted with sugar side chains, such as glucuronic acid (GlcA) and methylglucuronic acid (MeGlcA). It has recently been shown that muta...
SPRITE and ASSAM: web servers for side chain 3D-motif searching in protein structures
Nadzirin, Nurul; Gardiner, Eleanor J.; Willett, Peter; Artymiuk, Peter J.; Firdaus-Raih, Mohd
Similarities in the 3D patterns of amino acid side chains can provide insights into their function despite the absence of any detectable sequence or fold similarities. Search for protein sites (SPRITE) and amino acid pattern search for substructures and motifs (ASSAM) are graph theoretical programs that can search for 3D amino side chain matches in protein structures, by representing the amino acid side chains as pseudo-atoms. The geometric relationship of the pseudo-atoms to each other as a pattern can be represented as a labeled graph where the pseudo-atoms are the graph's nodes while the edges are the inter-pseudo-atomic distances. Both programs require the input file to be in the PDB format. The objective of using SPRITE is to identify matches of side chains in a query structure to patterns with characterized function. In contrast, a 3D pattern of interest can be searched for existing occurrences in available PDB structures using ASSAM. Both programs are freely accessible without any login requirement. SPRITE is available at http://mfrlab.org/grafss/sprite/ while ASSAM can be accessed at http://mfrlab.org/grafss/assam/. PMID:22573174
Synthesis and antiproliferativeactivity of new vinca alkaloids containing an α,β-unsaturated aromatic side chain.
Ngo, Quoc Anh; Nguyen, Le Anh; Vo, Ngoc Binh; Nguyen, Thuy Hang; Roussi, Fanny; Nguyen, The Hung; Nguyen, Van Tuyen
A new series of vinca-alkaloids derivatives containing various α,β-unsaturated aromatic side chains was synthesized. Four new vinca-alkaloids derivatives showed selective cytotoxicities against KB tumor cell lines with IC50 value below 0.1 μM, thus comparable with vinblastine. PMID:26522953
Improved Side Chain Dynamics in MARTINI Simulations of Protein-Lipid Interfaces.
Herzog, Florian A; Braun, Lukas; Schoen, Ingmar; Vogel, Viola
Specific interactions of protein side chains and lipid membranes regulate the localization, orientation, and activity of many peripheral proteins. Here, we introduce a modification of the coarse-grained MARTINI protein model, called 'side chain fix' (scFix), that was necessary and sufficient to correctly sample the side chain dynamics of β-strands in several globular proteins. When compared to μs long atomistic simulations or previous experimental findings, scFix MARTINI simulations reproduced all key interactions between the well-studied PLC-δ1 pleckstrin homology domain and a phosphatidylinositol-4,5-bisphosphate (PIP2) containing lipid membrane. Moreover, the extended runtime and higher sampling speed enabled the systematic mapping of the protein's rolling motion at the membrane, the identification of short-lived and stable binding orientations, as well as the verification and prediction of already known and of novel transient PIP2 binding sites. scFix also showed promise to maintain proper side chain orientation in other secondary structural motifs of the α-spectrin SH3 domain, the B1 domain of protein G, and the villin headpiece. This suggests that scFix improves on the predictive power of MARTINI simulations regarding protein-lipid and protein-ligand interactions. PMID:27042944
Thermochromism and structural change in polydiacetylenes including carboxy and 4-carboxyphenyl groups as the intermolecular hydrogen bond linkages in the side chain.
Tanioku, Chiaki; Matsukawa, Kimihiro; Matsumoto, Akikazu
We investigated the thermochromic behavior of polydiacetylenes including the carboxy and 4-carboxyphenyl groups as the side-chain substituents adjacent to the conjugated main chain, and then, the thermal stability and the thermochromism reversibility of the polymers were related to changes in the polymer conformations monitored by IR and Raman spectroscopies and powder X-ray diffractions. The polydiacetylenes with no or a phenylene spacer between the main chain and the carboxylic acid moiety were revealed to exhibit a thermal resistance for maintaining reversible thermochromism in a high temperature range, rather than polydiacetylenes with a conventional structure with a flexible alkylene spacer. The molecular stacking structures of the diacetylenes and the corresponding polymers in the crystals were discussed based on the results of an X-ray single-crystal structure analysis as well as the powder X-ray diffraction measurements. PMID:23276165
Energetic, Structural, and Antimicrobial Analyses of [beta]-Lactam Side Chain Recognition by [beta]-Lactamases
Caselli, E.; Powers, R.A.; Blaszczak, L.C.; Wu, C.Y.E.; Prati, F.; Shoichet, B.K.
Penicillins and cephalosporins are among the most widely used and successful antibiotics. The emergence of resistance to these {beta}-lactams, most often through bacterial expression of {beta}-lactamases, threatens public health. To understand how {beta}-lactamases recognize their substrates, it would be helpful to know their binding energies. Unfortunately, these have been difficult to measure because {beta}-lactams form covalent adducts with {beta}-lactamases. This has complicated functional analyses and inhibitor design. To investigate the contribution to interaction energy of the key amide (R1) side chain of {beta}-lactam antibiotics, eight acylglycineboronic acids that bear the side chains of characteristic penicillins and cephalosporins, as well as four other analogs, were synthesized. These transition-state analogs form reversible adducts with serine {beta}-lactamases. Therefore, binding energies can be calculated directly from K{sub i} values. The K{sub i} values measured span four orders of magnitude against the Group I {beta}-lactamase AmpC and three orders of magnitude against the Group II {beta}-lactamase TEM-1. The acylglycineboronic acids have K{sub i} values as low as 20 nM against AmpC and as low as 390 nM against TEM-1. The inhibitors showed little activity against serine proteases, such as chymotrypsin. R1 side chains characteristic of {beta}-lactam inhibitors did not have better affinity for AmpC than did side chains characteristic of {beta}-lactam substrates. Two of the inhibitors reversed the resistance of pathogenic bacteria to {beta}-lactams in cell culture. Structures of two inhibitors in their complexes with AmpC were determined by X-ray crystallography to 1.90 {angstrom} and 1.75 {angstrom} resolution; these structures suggest interactions that are important to the affinity of the inhibitors. Acylglycineboronic acids allow us to begin to dissect interaction energies between {beta}-lactam side chains and {beta}-lactamases. Surprisingly
Effect of the side-chain size on the optical and electrical properties of confined-PPV derivatives
NASA Astrophysics Data System (ADS)
Benzarti-Ghédira, Maha; Hrichi, Haikel; Jaballah, Nejmeddine; Ben Chaâbane, Rafik; Majdoub, Mustapha; Ben Ouada, Hafedh
We have investigated the influence of side-chain size on the optical and charge transport behavior of thin layers of new conjugated polymers based on separated PPV-type chromophores (P1, P2 and P3). The polymers are soluble in common organic solvents. The optical properties of these materials were investigated by UV-Vis absorption and PL spectroscopy. In thin solid films, the polymers show side-group dependent optical behavior; the PL spectra of polymers P2 and P3 showed a blue emission, whereas a green emission was observed for the polymer P1. The optical gaps of these thin layers have been estimated to be 2.93, 2.96 and 2.98 eV for P1, P2 and P3, respectively. The optical study showed a stronger π-π interaction in the P1 film. The electrical properties of ITO/PPV derivative/Al diodes base on these PPV derivatives were investigated by the current/tension characteristics and modeled by the current space-charge-limited (SCLC) mechanism; a higher mobility was obtained in the P2 thin layer. The morphology of the polymer films was studied and correlated to the optical and electrical properties.
Compliant random fields in gels formed from side-chain liquid crystalline polymers
NASA Astrophysics Data System (ADS)
Goldbart, Paul; Ye, Fangfu; Lu, Bing; Xing, Xiangjun
Localized polymer-chain backbones in gels formed from side-chain liquid crystalline polymers serve to create random fields that induce local orientational order of the nematogenic pendants of the side chains. These random fields differ, however, from conventional ones, in that they are compliant, and thus themselves undergo thermal fluctuations. We develop a free energy that describes local nematic ordering in presence of such compliant random fields. In particular, we show that, as a result of this compliance, the free energy has a qualitatively new structure, unattainable via truly static random fields. We discuss the physical implications this free energy, focusing on the consequences of the compliant nature of the random fields.
Arginine side chain interactions and the role of arginine as a gating charge carrier in voltage sensitive ion channels
Armstrong, Craig T.; Mason, Philip E.; Anderson, J. L. Ross; Dempsey, Christopher E.
Gating charges in voltage-sensing domains (VSD) of voltage-sensitive ion channels and enzymes are carried on arginine side chains rather than lysine. This arginine preference may result from the unique hydration properties of the side chain guanidinium group which facilitates its movement through a hydrophobic plug that seals the center of the VSD, as suggested by molecular dynamics simulations. To test for side chain interactions implicit in this model we inspected interactions of the side chains of arginine and lysine with each of the 19 non-glycine amino acids in proteins in the protein data bank. The arginine guanidinium interacts with non-polar aromatic and aliphatic side chains above and below the guanidinium plane while hydrogen bonding with polar side chains is restricted to in-plane positions. In contrast, non-polar side chains interact largely with the aliphatic part of the lysine side chain. The hydration properties of arginine and lysine are strongly reflected in their respective interactions with non-polar and polar side chains as observed in protein structures and in molecular dynamics simulations, and likely underlie the preference for arginine as a mobile charge carrier in VSD. PMID:26899474
Backbone dependency further improves side chain prediction efficiency in the Energy-based Conformer Library (bEBL).
Subramaniam, Sabareesh; Senes, Alessandro
Side chain optimization is an integral component of many protein modeling applications. In these applications, the conformational freedom of the side chains is often explored using libraries of discrete, frequently occurring conformations. Because side chain optimization can pose a computationally intensive combinatorial problem, the nature of these conformer libraries is important for ensuring efficiency and accuracy in side chain prediction. We have previously developed an innovative method to create a conformer library with enhanced performance. The Energy-based Library (EBL) was obtained by analyzing the energetic interactions between conformers and a large number of natural protein environments from crystal structures. This process guided the selection of conformers with the highest propensity to fit into spaces that should accommodate a side chain. Because the method requires a large crystallographic data-set, the EBL was created in a backbone-independent fashion. However, it is well established that side chain conformation is strongly dependent on the local backbone geometry, and that backbone-dependent libraries are more efficient in side chain optimization. Here we present the backbone-dependent EBL (bEBL), whose conformers are independently sorted for each populated region of Ramachandran space. The resulting library closely mirrors the local backbone-dependent distribution of side chain conformation. Compared to the EBL, we demonstrate that the bEBL uses fewer conformers to produce similar side chain prediction outcomes, thus further improving performance with respect to the already efficient backbone-independent version of the library. PMID:25212195
Arginine side chain interactions and the role of arginine as a gating charge carrier in voltage sensitive ion channels
NASA Astrophysics Data System (ADS)
Armstrong, Craig T.; Mason, Philip E.; Anderson, J. L. Ross; Dempsey, Christopher E.
Gating charges in voltage-sensing domains (VSD) of voltage-sensitive ion channels and enzymes are carried on arginine side chains rather than lysine. This arginine preference may result from the unique hydration properties of the side chain guanidinium group which facilitates its movement through a hydrophobic plug that seals the center of the VSD, as suggested by molecular dynamics simulations. To test for side chain interactions implicit in this model we inspected interactions of the side chains of arginine and lysine with each of the 19 non-glycine amino acids in proteins in the protein data bank. The arginine guanidinium interacts with non-polar aromatic and aliphatic side chains above and below the guanidinium plane while hydrogen bonding with polar side chains is restricted to in-plane positions. In contrast, non-polar side chains interact largely with the aliphatic part of the lysine side chain. The hydration properties of arginine and lysine are strongly reflected in their respective interactions with non-polar and polar side chains as observed in protein structures and in molecular dynamics simulations, and likely underlie the preference for arginine as a mobile charge carrier in VSD.
Understanding the physical basis for the side-chain conformational preferences of methionine.
Virrueta, Alejandro; O'Hern, Corey S; Regan, Lynne
Methionine (Met) is a structurally versatile amino acid most commonly found in protein cores and at protein-protein interfaces. Thus, a complete description of the structure of Met is important for a fundamental understanding of protein structure and design. In previous work, we showed that the hard-sphere dipeptide model is able to recapitulate the side-chain dihedral angle distributions observed in high-resolution protein crystal structures for the nine amino acids we have studied to date: Val, Thr, Ser, Leu, Ile, Cys, Tyr, Trp, and Phe. Using the same approach, we are also able to predict the observed χ1 and χ2 side-chain dihedral angle distributions for Met. However, the form of the side-chain dihedral angle distribution P(χ3 ) predicted by the hard-sphere model does not match the observed distribution. We investigate the possible origins of the discrepancy and find that specific bond lengths and angles in Met side chains strongly influence P(χ3 ). We then identify minimal additions to the hard-sphere dipeptide model necessary to quantitatively predict P(χ3 ) of Met, and its near isosteres norleucine (Nle) and selenomethionine (Mse). We find that adding weak attractive interactions between hydrogen atoms to the model is sufficient to achieve predictions for P(χ3 ) that closely match the observed P(χ3 ) distributions for Met, Nle, and Mse. We explicitly show that weak attractive interactions between hydrogens do not negatively affect the agreement between the predicted and observed side-chain dihedral angle distribution for Val, Leu, Ile, and Phe, as we expect for other amino acids. Proteins 2016; 84:900-911. © 2016 Wiley Periodicals, Inc. PMID:26917446
Self-assembly and adsorption properties of Fmoc-substituted short peptide bearing charged side chains
NASA Astrophysics Data System (ADS)
Nakayama, Toru; Sakuraba, Taro; Yamamoto, Yohei
Charge-separated peptide β-sheet with a positive charge on one side and a negative charge on the other side adsorbed on a mica surface with well-ordered geometry along the crystallographic direction of the mica surface. In MeOH and MeOH/H2O mixed solvent, the peptides do not form β-sheet structure. During the evaporation process of the solvent on a mica substrate, the peptides self-assembled to form β-sheet and adsorb on the surface via electrostatic interaction between negative charge of the mica surface and positive charge of the lysine side chain on one side of the β-sheet.
Novel Fluorinated Polymers Containing Short Perfluorobutyl Side Chains and Their Super Wetting Performance on Diverse Substrates.
Jiang, Jingxian; Zhang, Guangfa; Wang, Qiongyan; Zhang, Qinghua; Zhan, Xiaoli; Chen, Fengqiu
Because the emission of perfluorooctanoic acid (PFOA) was completely prohibited in 2015, the widely used poly- and perfluoroalkyl substances with long perfluoroalkyl groups must be substituted by environmentally friendly alternatives. In this study, one kind of potential alternative (i.e., fluorinated polymers with short perfluorobutyl side chains) has been synthesized from the prepared monomers {i.e., (perfluorobutyl)ethyl acrylate (C4A), (perfluorobutyl)ethyl methacrylate (C4MA), 2-[[[[2-(perfluorobutyl)]sulfonyl]methyl]amino]ethyl acrylate (C4SA), and methacrylate (C4SMA)}, and the microstructure, super wetting performance, and applications of the synthesized fluorinated polymers were systematically investigated. The thermal and crystallization behaviors of the fluoropolymer films were characterized by differential scanning calorimetry and wide-angle X-ray diffraction analysis, respectively. Dynamic water-repellent models were constructed. The stable low surface energy and dynamic water- and oil-repellent properties of these synthesized fluorinated polymers with short perfluorobutyl side chains were attributed to the synergetic effect of amorphous fluorinated side chains in perfluoroalkyl acrylate and crystalline hydrocarbon pendant groups in stearyl acrylate. Outstanding water- and oil-repellent properties of fabrics and any other substrates could be achieved by a facile dip-coating treatment using a fluorinated copolymer dispersion. As a result, we believe that our prepared fluorinated copolymers are potential candidates to replace the fluoroalkylated polymers with long perfluorinated chains in nonstick and self-cleaning applications in our daily life. PMID:27052113
Producing high-accuracy lattice models from protein atomic coordinates including side chains.
Mann, Martin; Saunders, Rhodri; Smith, Cameron; Backofen, Rolf; Deane, Charlotte M
Lattice models are a common abstraction used in the study of protein structure, folding, and refinement. They are advantageous because the discretisation of space can make extensive protein evaluations computationally feasible. Various approaches to the protein chain lattice fitting problem have been suggested but only a single backbone-only tool is available currently. We introduce LatFit, a new tool to produce high-accuracy lattice protein models. It generates both backbone-only and backbone-side-chain models in any user defined lattice. LatFit implements a new distance RMSD-optimisation fitting procedure in addition to the known coordinate RMSD method. We tested LatFit's accuracy and speed using a large nonredundant set of high resolution proteins (SCOP database) on three commonly used lattices: 3D cubic, face-centred cubic, and knight's walk. Fitting speed compared favourably to other methods and both backbone-only and backbone-side-chain models show low deviation from the original data (~1.5 Å RMSD in the FCC lattice). To our knowledge this represents the first comprehensive study of lattice quality for on-lattice protein models including side chains while LatFit is the only available tool for such models. PMID:22934109
Producing High-Accuracy Lattice Models from Protein Atomic Coordinates Including Side Chains
Mann, Martin; Saunders, Rhodri; Smith, Cameron; Backofen, Rolf; Deane, Charlotte M.
Lattice models are a common abstraction used in the study of protein structure, folding, and refinement. They are advantageous because the discretisation of space can make extensive protein evaluations computationally feasible. Various approaches to the protein chain lattice fitting problem have been suggested but only a single backbone-only tool is available currently. We introduce LatFit, a new tool to produce high-accuracy lattice protein models. It generates both backbone-only and backbone-side-chain models in any user defined lattice. LatFit implements a new distance RMSD-optimisation fitting procedure in addition to the known coordinate RMSD method. We tested LatFit's accuracy and speed using a large nonredundant set of high resolution proteins (SCOP database) on three commonly used lattices: 3D cubic, face-centred cubic, and knight's walk. Fitting speed compared favourably to other methods and both backbone-only and backbone-side-chain models show low deviation from the original data (~1.5 Å RMSD in the FCC lattice). To our knowledge this represents the first comprehensive study of lattice quality for on-lattice protein models including side chains while LatFit is the only available tool for such models. PMID:22934109
The binding of analogs of porphyrins and chlorins with elongated side chains to albumin.
Ben Dror, Shimshon; Bronshtein, Irena; Weitman, Hana; Smith, Kevin M; O'Neal, William G; Jacobi, Peter A; Ehrenberg, Benjamin
In previous studies, we demonstrated that elongation of side chains of several sensitizers endowed them with higher affinity for artificial and natural membranes and caused their deeper localization in membranes. In the present study, we employed eight hematoporphyrin and protoporphyrin analogs and four groups containing three chlorin analogs each, all synthesized with variable numbers of methylenes in their alkyl carboxylic chains. We show that these tetrapyrroles' affinity for bovine serum albumin (BSA) and their localization in the binding site are also modulated by chain lengths. The binding constants of the hematoporphyrins and protoporphyrins to BSA increased as the number of methylenes was increased. The binding of the chlorins depended on the substitution at the meso position opposite to the chains. The quenching of the sensitizers' florescence by external iodide ions decreased as the side chains became longer, indicating to deeper insertion of the molecules into the BSA binding pocket. To corroborate this conclusion, we studied the efficiency of photodamage caused to tryptophan in BSA upon illumination of the bound sensitizers. The efficiency was found to depend on the side-chain lengths of the photosensitizer. We conclude that the protein site that hosts these sensitizers accommodates different analogs at positions that differ slightly from each other. These differences are manifested in the ease of access of iodide from the external aqueous phase, and in the proximity of the photosensitizers to the tryptophan. In the course of this study, we developed the kinetic equations that have to be employed when the sensitizer itself is being destroyed. PMID:19330323
Equilibrium and shear-induced conformations of a side-chain liquid crystal polymer
NASA Astrophysics Data System (ADS)
Castelletto, V.; Noirez, L.; Vigoureux, P.
These studies delineate the conformations adopted by a side-chain liquid-crystalline polymer subjected to a steady-state shear flow as well as the corresponding me so pha se director orientations. Two distinct director orientations are identified in the nematic phase, giving evidence of a shear-induced transition from a flow-aligning to a non flow-aligning behavior. This transition coincides, at rest, with a subtle change from prolate to oblate polymer main-chain conformation. In the smectic phase, the layers form multilayer cylinders oriented along the velocity axis.
Synthesis of enones, pyrazolines and pyrrolines with gem-difluoroalkyl side chains
El Dine, Assaad Nasr; Khalaf, Ali; Grée, Danielle; Tasseau, Olivier; Fares, Fares; Jaber, Nada; Lesot, Philippe
Summary Starting from easily accessible gem-difluoropropargylic derivatives, a DBU-mediated isomerisation affords enones in fair yields with a gem-difluoroalkyl chain. These derivatives were used to prepare pyrazolines and pyrrolines with the desired gem-difluoroalkyl side chain by cyclocondensations in good yields and with excellent stereoselectivity. A one-pot process was also successfully developed for these sequential reactions. By carrying out various types of Pd-catalyzed coupling reactions for compounds with a p-bromophenyl substituent a route to focused chemical libraries was demonstrated. PMID:24204405
Synthesis of enones, pyrazolines and pyrrolines with gem-difluoroalkyl side chains.
El Dine, Assaad Nasr; Khalaf, Ali; Grée, Danielle; Tasseau, Olivier; Fares, Fares; Jaber, Nada; Lesot, Philippe; Hachem, Ali; Grée, René
Starting from easily accessible gem-difluoropropargylic derivatives, a DBU-mediated isomerisation affords enones in fair yields with a gem-difluoroalkyl chain. These derivatives were used to prepare pyrazolines and pyrrolines with the desired gem-difluoroalkyl side chain by cyclocondensations in good yields and with excellent stereoselectivity. A one-pot process was also successfully developed for these sequential reactions. By carrying out various types of Pd-catalyzed coupling reactions for compounds with a p-bromophenyl substituent a route to focused chemical libraries was demonstrated. PMID:24204405
Use of antibody gene library for the isolation of specific single chain antibodies by ampicillin-antigen conjugates.
Neumann-Schaal, Meina; Messerschmidt, Katrin; Grenz, Nicole; Heilmann, Katja
Isolation of recombinant antibodies from antibody libraries is commonly performed by different molecular display formats including phage display and ribosome display or different cell-surface display formats. We describe a new method which allows the selection of Escherichia coli cells producing the required single chain antibody by cultivation in presence of ampicillin conjugated to the antigen of interest. The method utilizes the neutralization of the conjugate by the produced single chain antibody which is secreted to the periplasm. Therefore, a new expression system based on the pET26b vector was designed and a library was constructed. The method was successfully established first for the selection of E. coli BL21 Star (DE3) cells expressing a model single chain antibody (anti-fluorescein) by a simple selection assay on LB-agar plates. Using this selection assay, we could identify a new single chain antibody binding biotin by growing E. coli BL21 Star (DE3) containing the library in presence of a biotin-ampicillin conjugate. In contrast to methods as molecular or cell surface display our selection system applies the soluble single chain antibody molecule and thereby avoids undesired effects, e.g. by the phage particle or the yeast fusion protein. By selecting directly in an expression strain, production and characterization of the selected single chain antibody is possible without any further cloning or transformation steps. PMID:23453960
Correlation between protein secondary structure, backbone bond angles, and side-chain orientations
NASA Astrophysics Data System (ADS)
Lundgren, Martin; Niemi, Antti J.
We investigate the fine structure of the sp3 hybridized covalent bond geometry that governs the tetrahedral architecture around the central Cα carbon of a protein backbone, and for this we develop new visualization techniques to analyze high-resolution x-ray structures in the Protein Data Bank. We observe that there is a correlation between the deformations of the ideal tetrahedral symmetry and the local secondary structure of the protein. We propose a universal coarse-grained energy function to describe the ensuing side-chain geometry in terms of the Cβ carbon orientations. The energy function can model the side-chain geometry with a subatomic precision. As an example we construct the Cα-Cβ structure of HP35 chicken villin headpiece. We obtain a configuration that deviates less than 0.4 Å in root-mean-square distance from the experimental x-ray structure.
Optical probe for the cytochrome P-450 cholesterol side chain cleavage enzyme
Marrone, Babetta L.; Simpson, Daniel J.; Unkefer, Clifford J.; Whaley, Thomas W.
An optical probe enables the study of enzyme activity by absorbance spectroscopy or by sensitive fluorescence methods. In particular, the probe provides the ability to monitor the activity of cytochrome P-450.sub.scc enzyme, the rate limiting enzyme for steroid biosynthesis. Located on the inner mitochondrial membrane, P-450.sub.scc catalyzes the conversion of cholesterol to pregnenolone and isocapraldehyde by sequential oxidations of the cholesterol side chain. The fluorogenic probe includes a cholesterol-like steroid linked to a chromophore through a linking group. The chromophore is selected to have little optical response when linked to the steroid substrate and an enhanced optical response when cleaved from the substrate and linking group. Thus, a fluorescent anion that can be optically detected is generated by the side-chain cleavage reaction during steroidogenesis.
Optical probe for the cytochrome P-450 cholesterol side chain cleavage enzyme
Marrone, Babetta L.; Simpson, Daniel J.; Unkefer, Clifford J.; Whaley, Thomas W.
An optical probe enables the study of enzyme activity by absorbance spectroscopy or by sensitive fluorescence methods. In particular, the probe provides the ability to monitor the activity of cytochrome P-450.sub.scc enzyme, the rate limiting enzyme for steroid biosynthesis. Located on the inner mitochondrial membrane, P-450.sub.scc catalyzes the conversion of cholesterol to pregnenolone and isocapraldehyde by sequential oxidations of the cholesterol side chain. The fluorogenic probe includes a cholesterol-like steroid linked to a chromophore through a linking group. The chromophore is selected to have little optical response when linked to the steroid substrate and an enhanced optical response when cleaved from the substrate and linking group. Thus, a fluorescent anion that can be optically detected is generated by the side-chain cleavage reaction during steroidogenesis.
Radical Additions to Aromatic Residues in Peptides Facilitate Unexpected Side Chain and Backbone Losses
NASA Astrophysics Data System (ADS)
Zhang, Xing; Julian, Ryan R.
Accurate identification of fragments in tandem mass spectrometry experiments is aided by knowledge of relevant fragmentation mechanisms. Herein, novel radical addition reactions that direct unexpected side-chain dissociations at tryptophan and tyrosine residues are reported. Various mechanisms that can account for the observed dissociation channels are investigated by experiment and theory. The propensity for radical addition at a particular site is found to be primarily under kinetic control, which is largely dictated by molecular structure. In certain peptides, intramolecular radical addition reactions are favored, which leads to the observation of numerous unexpected fragments. In one pathway, radical addition leads to migration of an aromatic side chain to another residue. Alternatively, radical addition followed by hydrogen atom loss leads to cyclization of the peptide and increased observation of internal sequence fragments. Radical addition reactions should be considered when assigning fragmentation spectra obtained from activation of hydrogen deficient peptides.
Optical probe for the cytochrome P-450 cholesterol side chain cleavage enzyme
Marrone, B.L.; Simpson, D.J.; Unkefer, C.J.; Whaley, T.W.
An optical probe enables the study of enzyme activity by absorbance spectroscopy or by sensitive fluorescence methods. In particular, the probe provides the ability to monitor the activity of cytochrome P-450[sub scc] enzyme, the rate limiting enzyme for steroid biosynthesis. Located on the inner mitochondrial membrane, P-450[sub scc] catalyzes the conversion of cholesterol to prednesolone and isocapraldehyde by sequential oxidations of the cholesterol side chain. The fluorogenic probe includes a cholesterol-like steroid linked to a chromophore through a linking group. The chromophore is selected to have little optical response when linked to the steroid substrate and an enhanced optical response when cleaved from the substrate and linking group. Thus, a fluorescent anion that can be optically detected is generated by the side-chain cleavage reaction during steroidogenesis.
Structure–Activity Relationships for Side Chain Oxysterol Agonists of the Hedgehog Signaling Pathway
Oxysterols (OHCs) are byproducts of cholesterol oxidation that are known to activate the Hedeghog (Hh) signaling pathway. While OHCs that incorporate hydroxyl groups throughout the scaffold are known, those that act as agonists of Hh signaling primarily contain a single hydroxyl on the alkyl side chain. We sought to further explore how side chain hydroxylation patterns affect oxysterol-mediated Hh activation, by performing a structure–activity relationship study on a series of synthetic OHCs. The most active analogue, 23(R)-OHC (35), demonstrated potent activation of Hh signaling in two Hh-dependent cell lines (EC50 values 0.54–0.65 μM). In addition, OHC 35 was approximately 3-fold selective for the Hh pathway as compared to the liver X receptor, a nuclear receptor that is also activated by endogenous OHCs. Finally, 35 induced osteogenic differentiation and osteoblast formation in cultured cells, indicating functional agonism of the Hh pathway. PMID:24900386
The lipopolysaccharide O side chain of Vibrio vulnificus serogroup E is a virulence determinant for eels.
Amaro, C; Fouz, B; Biosca, E G; Marco-Noales, E; Collado, R
Vibrio vulnificus is a gram-negative bacterium capable of producing septicemic infections in eels and immunocompromised humans. Two biotypes are classically recognized, with the virulence for eels being specific to strains belonging to biotype 2, which constitutes a homogeneous lipopolysaccharide (LPS)-based O serogroup (which we have designated serogroup E). In the present study we demonstrated that the O side chain of this LPS determines the selective virulence of biotype 2 for eels: (i) biotype 1 strains (which do not belong to serogroup E) are destroyed by the bactericidal action of nonimmune eel serum (NIS) through activation of the alternative pathway of complement, (ii) biotype 2 strains (of serogroup E) are resistant to NIS, and (iii) rough mutants of biotype 2 lacking the O polysaccharide side chain are sensitive to NIS and avirulent for eels. PMID:9169795
IMAAAGINE: a webserver for searching hypothetical 3D amino acid side chain arrangements in the Protein Data Bank.
Nadzirin, Nurul; Willett, Peter; Artymiuk, Peter J; Firdaus-Raih, Mohd
We describe a server that allows the interrogation of the Protein Data Bank for hypothetical 3D side chain patterns that are not limited to known patterns from existing 3D structures. A minimal side chain description allows a variety of side chain orientations to exist within the pattern, and generic side chain types such as acid, base and hydroxyl-containing can be additionally deployed in the search query. Moreover, only a subset of distances between the side chains need be specified. We illustrate these capabilities in case studies involving arginine stacks, serine-acid group arrangements and multiple catalytic triad-like configurations. The IMAAAGINE server can be accessed at http://mfrlab.org/grafss/imaaagine/. PMID:23716645
Quantitative Profiling of Feruloylated Arabinoxylan Side-Chains from Graminaceous Cell Walls.
Schendel, Rachel R; Meyer, Marleen R; Bunzel, Mirko
Graminaceous arabinoxylans are distinguished by decoration with feruloylated monosaccharidic and oligosaccharidic side-chains. Although it is hypothesized that structural complexity and abundance of these feruloylated arabinoxylan side-chains may contribute, among other factors, to resistance of plant cell walls to enzymatic degradation, quantitative profiling approaches for these structural units in plant cell wall materials have not been described yet. Here we report the development and application of a rapid and robust method enabling the quantitative comparison of feruloylated side-chain profiles in cell wall materials following mildly acidic hydrolysis, C18-solid phase extraction (SPE), reduction under aprotic conditions, and liquid chromatography with diode-array detection/mass spectrometry (LC-DAD/MS) separation and detection. The method was applied to the insoluble fiber/cell wall materials isolated from 12 whole grains: wild rice (Zizania aquatica L.), long-grain brown rice (Oryza sativa L.), rye (Secale cereale L.), kamut (Triticum turanicum Jakubz.), wheat (Triticum aestivum L.), spelt (Triticum spelta L.), intermediate wheatgrass (Thinopyrum intermedium), maize (Zea mays L.), popcorn (Zea mays L. var. everta), oat (Avena sativa L.) (dehulled), barley (Hordeum vulgare L.) (dehulled), and proso millet (Panicum miliaceum L.). Between 51 and 96% of the total esterified monomeric ferulates were represented in the quantified compounds captured in the feruloylated side-chain profiles, which confirms the significance of these structures to the global arabinoxylan structure in terms of quantity. The method provided new structural insights into cereal grain arabinoxylans, in particular, that the structural moiety α-l-galactopyranosyl-(1→2)-β-d-xylopyranosyl-(1→2)-5-O-trans-feruloyl-l-arabinofuranose (FAXG), which had previously only been described in maize, is ubiquitous to cereal grains. PMID:26834763
Statistical mechanics of protein allostery: Roles of backbone and side-chain structural fluctuations
NASA Astrophysics Data System (ADS)
Itoh, Kazuhito; Sasai, Masaki
A statistical mechanical model of allosteric transition of proteins is developed by extending the structure-based model of protein folding to cases that a protein has two different native conformations. Partition function is calculated exactly within the model and free-energy surfaces associated with allostery are derived. In this paper, the model of allosteric transition proposed in a previous paper [Proc. Natl. Acad. Sci. U.S.A 134, 7775 (2010)] is reformulated to describe both fluctuation in side-chain configurations and that in backbone structures in a balanced way. The model is applied to example proteins, Ras, calmodulin, and CheY: Ras undergoes the allosteric transition between guanosine diphosphate (GDP)-bound and guanosine triphosphate (GTP)-bound forms, and the model results show that the GDP-bound form is stabilized enough to prevent unnecessary signal transmission, but the conformation in the GTP-bound state bears large fluctuation in side-chain configurations, which may help to bind multiple target proteins for multiple pathways of signaling. The calculated results of calmodulin show the scenario of sequential ordering in Ca2 + binding and the associated allosteric conformational change, which are realized though the sequential appearing of pre-existing structural fluctuations, i.e., fluctuations to show structures suitable to bind Ca2 + before its binding. Here, the pre-existing fluctuations to accept the second and third Ca2 + ions are dominated by the side-chain fluctuation. In CheY, the calculated side-chain fluctuation of Tyr106 is coordinated with the backbone structural change in the β4-α4 loop, which explains the pre-existing Y-T coupling process in this protein. Ability of the model to explain allosteric transitions of example proteins supports the view that the large entropic effects lower the free-energy barrier of allosteric transition.
Communication: Accurate determination of side-chain torsion angle χ1 in proteins: Phenylalanine residues
NASA Astrophysics Data System (ADS)
Suardíaz, R.; Crespo-Otero, R.; Pérez, C.; Fabián, J. San; de la Vega, J. M. García
Quantitative side-chain torsion angle χ1 determinations of phenylalanine residues in Desulfovibrio vulgaris flavodoxin are carried out using exclusively the correlation between the experimental vicinal coupling constants and theoretically determined Karplus equations. Karplus coefficients for nine vicinal coupling related with the torsion angle χ1 were calculated using the B3LYP functional and basis sets of different size. Optimized χ1 angles are in outstanding agreement with those previously reported by employing x ray and NMR measurements.
Fitmunk: improving protein structures by accurate, automatic modeling of side-chain conformations.
Porebski, Przemyslaw Jerzy; Cymborowski, Marcin; Pasenkiewicz-Gierula, Marta; Minor, Wladek
Improvements in crystallographic hardware and software have allowed automated structure-solution pipelines to approach a near-`one-click' experience for the initial determination of macromolecular structures. However, in many cases the resulting initial model requires a laborious, iterative process of refinement and validation. A new method has been developed for the automatic modeling of side-chain conformations that takes advantage of rotamer-prediction methods in a crystallographic context. The algorithm, which is based on deterministic dead-end elimination (DEE) theory, uses new dense conformer libraries and a hybrid energy function derived from experimental data and prior information about rotamer frequencies to find the optimal conformation of each side chain. In contrast to existing methods, which incorporate the electron-density term into protein-modeling frameworks, the proposed algorithm is designed to take advantage of the highly discriminatory nature of electron-density maps. This method has been implemented in the program Fitmunk, which uses extensive conformational sampling. This improves the accuracy of the modeling and makes it a versatile tool for crystallographic model building, refinement and validation. Fitmunk was extensively tested on over 115 new structures, as well as a subset of 1100 structures from the PDB. It is demonstrated that the ability of Fitmunk to model more than 95% of side chains accurately is beneficial for improving the quality of crystallographic protein models, especially at medium and low resolutions. Fitmunk can be used for model validation of existing structures and as a tool to assess whether side chains are modeled optimally or could be better fitted into electron density. Fitmunk is available as a web service at http://kniahini.med.virginia.edu/fitmunk/server/ or at http://fitmunk.bitbucket.org/. PMID:26894674
Quantitative Profiling of Feruloylated Arabinoxylan Side-Chains from Graminaceous Cell Walls
Schendel, Rachel R.; Meyer, Marleen R.; Bunzel, Mirko
Graminaceous arabinoxylans are distinguished by decoration with feruloylated monosaccharidic and oligosaccharidic side-chains. Although it is hypothesized that structural complexity and abundance of these feruloylated arabinoxylan side-chains may contribute, among other factors, to resistance of plant cell walls to enzymatic degradation, quantitative profiling approaches for these structural units in plant cell wall materials have not been described yet. Here we report the development and application of a rapid and robust method enabling the quantitative comparison of feruloylated side-chain profiles in cell wall materials following mildly acidic hydrolysis, C18-solid phase extraction (SPE), reduction under aprotic conditions, and liquid chromatography with diode-array detection/mass spectrometry (LC-DAD/MS) separation and detection. The method was applied to the insoluble fiber/cell wall materials isolated from 12 whole grains: wild rice (Zizania aquatica L.), long-grain brown rice (Oryza sativa L.), rye (Secale cereale L.), kamut (Triticum turanicum Jakubz.), wheat (Triticum aestivum L.), spelt (Triticum spelta L.), intermediate wheatgrass (Thinopyrum intermedium), maize (Zea mays L.), popcorn (Zea mays L. var. everta), oat (Avena sativa L.) (dehulled), barley (Hordeum vulgare L.) (dehulled), and proso millet (Panicum miliaceum L.). Between 51 and 96% of the total esterified monomeric ferulates were represented in the quantified compounds captured in the feruloylated side-chain profiles, which confirms the significance of these structures to the global arabinoxylan structure in terms of quantity. The method provided new structural insights into cereal grain arabinoxylans, in particular, that the structural moiety α-l-galactopyranosyl-(1→2)-β-d-xylopyranosyl-(1→2)-5-O-trans-feruloyl-l-arabinofuranose (FAXG), which had previously only been described in maize, is ubiquitous to cereal grains. PMID:26834763
The role of cystic fibrosis transmembrane conductance regulator phenylalanine 508 side chain in ion channel gating.
Cui, Liying; Aleksandrov, Luba; Hou, Yue-Xian; Gentzsch, Martina; Chen, Jey-Hsin; Riordan, John R; Aleksandrov, Andrei A
Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel employing the ABC transporter structural motif. Deletion of a single residue (Phe508) in the first nucleotide-binding domain (NBD1), which occurs in most patients with cystic fibrosis, impairs both maturation and function of the protein. However, substitution of the Phe508 with small uncharged amino acids, including cysteine, is permissive for maturation. To explore the possible role of the phenylalanine aromatic side chain in channel gating we introduced a cysteine at this position in cysless CFTR, enabling its selective chemical modification by sulfhydryl reagents. Both cysless and wild-type CFTR ion channels have identical mean open times when activated by different nucleotide ligands. Moreover, both channels could be locked in an open state by introducing an ATPase inhibiting mutation (E1371S). However, the introduction of a single cysteine (F508C) prevented the cysless E1371S channel from maintaining the permanently open state, allowing closing to occur. Chemical modification of cysless E1371S/F508C by sulfhydryl reagents was used to probe the role of the side chain in ion channel function. Specifically, benzyl-methanethiosulphonate modification of this variant restored the gating behaviour to that of cysless E1371S containing the wild-type phenylalanine at position 508. This provides the first direct evidence that a specific interaction of the Phe508 aromatic side chain plays a role in determining the residency time in the closed state. Thus, despite the fact that this aromatic side chain is not essential for CFTR folding, it is important in the ion channel function. PMID:16484308
The role of cystic fibrosis transmembrane conductance regulator phenylalanine 508 side chain in ion channel gating
Cui, Liying; Aleksandrov, Luba; Hou, Yue-Xian; Gentzsch, Martina; Chen, Jey-Hsin; Riordan, John R; Aleksandrov, Andrei A
Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel employing the ABC transporter structural motif. Deletion of a single residue (Phe508) in the first nucleotide-binding domain (NBD1), which occurs in most patients with cystic fibrosis, impairs both maturation and function of the protein. However, substitution of the Phe508 with small uncharged amino acids, including cysteine, is permissive for maturation. To explore the possible role of the phenylalanine aromatic side chain in channel gating we introduced a cysteine at this position in cysless CFTR, enabling its selective chemical modification by sulfhydryl reagents. Both cysless and wild-type CFTR ion channels have identical mean open times when activated by different nucleotide ligands. Moreover, both channels could be locked in an open state by introducing an ATPase inhibiting mutation (E1371S). However, the introduction of a single cysteine (F508C) prevented the cysless E1371S channel from maintaining the permanently open state, allowing closing to occur. Chemical modification of cysless E1371S/F508C by sulfhydryl reagents was used to probe the role of the side chain in ion channel function. Specifically, benzyl-methanethiosulphonate modification of this variant restored the gating behaviour to that of cysless E1371S containing the wild-type phenylalanine at position 508. This provides the first direct evidence that a specific interaction of the Phe508 aromatic side chain plays a role in determining the residency time in the closed state. Thus, despite the fact that this aromatic side chain is not essential for CFTR folding, it is important in the ion channel function. PMID:16484308
Backbone and side chain NMR assignments for the ribosome assembly factor Nop6 from Saccharomyces cerevisiae.
Wurm, Jan Philip; Lioutikov, Anatoli; Kötter, Peter; Entian, Karl-Dieter; Wöhnert, Jens
The Saccharomyces cerevisiae Nop6 protein is involved in the maturation of the small ribosomal subunit. It contains a central RNA binding domain and a predicted C-terminal coiled-coil domain. Here we report the almost complete (>90%) (1)H,(13)C,(15)N backbone and side chain NMR assignment of a 15 kDa Nop6 construct comprising the RNA binding and coiled-coil domains. PMID:23921755
Preliminary assessment of the C13-side chain 2'-hydroxylase involved in taxol biosynthesis.
Long, Robert M; Croteau, Rodney
The biosynthesis of the anticancer drug Taxol in yew (Taxus) species is thought to involve the preliminary formation of the advanced taxane diterpenoid intermediate baccatin III upon which the functionally important N-benzoyl phenylisoserinoyl side chain is subsequently assembled at the C13-O-position. In vivo feeding studies with Taxus tissues and characterization of the two transferases responsible for C13-side chain construction have suggested a sequential process in which an aminomutase converts alpha-phenylalanine to beta-phenylalanine which is then activated to the corresponding CoA ester and transferred to baccatin III to yield beta-phenylalanoyl baccatin III (i.e., N-debenzoyl-2'-deoxytaxol) that undergoes subsequent 2'-hydroxylation and N-benzoylation to afford Taxol. However, because the side chain transferase can utilize both beta-phenylalanoyl CoA and phenylisoserinoyl CoA in the C13-O-esterification of baccatin III, ambiguity remained as to whether the 2'-hydroxylation step occurs before or after transfer of the amino phenylpropanoyl moiety. Using cell-free enzyme systems from Taxus suspension cells, no evidence was found for the direct hydroxylation of beta-phenylalanine to phenylisoserine; however, microsomal preparations from this tissue appeared capable of the cytochrome P450-mediated hydroxylation of beta-phenylalanoyl baccatin III to phenylisoserinoyl baccatin III (i.e., N-debenzoyltaxol) as the penultimate step in the formation of Taxol and related N-substituted taxoids. These preliminary results, which are consistent with the proposed side chain assembly process, have clarified an important step of Taxol biosynthesis and set the foundation for cloning the responsible cytochrome P450 hydroxylase gene. PMID:16137660
Preliminary assessment of the C13-side chain 2'-hydroxylase involved in Taxol biosynthesis
Long, Robert M.; Croteau, Rodney . E-mail: email@example.com
The biosynthesis of the anticancer drug Taxol in yew (Taxus) species is thought to involve the preliminary formation of the advanced taxane diterpenoid intermediate baccatin III upon which the functionally important N-benzoyl phenylisoserinoyl side chain is subsequently assembled at the C13-O-position. In vivo feeding studies with Taxus tissues and characterization of the two transferases responsible for C13-side chain construction have suggested a sequential process in which an aminomutase converts {alpha}-phenylalanine to {beta}-phenylalanine which is then activated to the corresponding CoA ester and transferred to baccatin III to yield {beta}-phenylalanoyl baccatin III (i.e., N-debenzoyl-2'-deoxytaxol) that undergoes subsequent 2'-hydroxylation and N-benzoylation to afford Taxol. However, because the side chain transferase can utilize both {beta}-phenylalanoyl CoA and phenylisoserinoyl CoA in the C13-O-esterification of baccatin III, ambiguity remained as to whether the 2'-hydroxylation step occurs before or after transfer of the amino phenylpropanoyl moiety. Using cell-free enzyme systems from Taxus suspension cells, no evidence was found for the direct hydroxylation of {beta}-phenylalanine to phenylisoserine; however, microsomal preparations from this tissue appeared capable of the cytochrome P450-mediated hydroxylation of {beta}-phenylalanoyl baccatin III to phenylisoserinoyl baccatin III (i.e., N-debenzoyltaxol) as the penultimate step in the formation of Taxol and related N-substituted taxoids. These preliminary results, which are consistent with the proposed side chain assembly process, have clarified an important step of Taxol biosynthesis and set the foundation for cloning the responsible cytochrome P450 hydroxylase gene.
Improved prediction of protein side-chain conformations with SCWRL4
Krivov, Georgii G.; Shapovalov, Maxim V.; Dunbrack, Roland L.
Determination of side-chain conformations is an important step in protein structure prediction and protein design. Many such methods have been presented, although only a small number are in widespread use. SCWRL is one such method, and the SCWRL3 program (2003) has remained popular due to its speed, accuracy, and ease-of-use for the purpose of homology modeling. However, higher accuracy at comparable speed is desirable. This has been achieved through: 1) a new backbone-dependent rotamer library based on kernel density estimates; 2) averaging over samples of conformations about the positions in the rotamer library; 3) a fast anisotropic hydrogen bonding function; 4) a short-range, soft van der Waals atom-atom interaction potential; 5) fast collision detection using k-discrete oriented polytopes; 6) a tree decomposition algorithm to solve the combinatorial problem; and 7) optimization of all parameters by determining the interaction graph within the crystal environment using symmetry operators of the crystallographic space group. Accuracies as a function of electron density of the side chains demonstrate that side chains with higher electron density are easier to predict than those with low electron density and presumed conformational disorder. For a testing set of 379 proteins, 86% of χ1 angles and 75% of χ1+2 are predicted correctly within 40° of the X-ray positions. Among side chains with higher electron density (25th–100th percentile), these numbers rise to 89% and 80%. The new program maintains its simple command-line interface, designed for homology modeling, and is now available as a dynamic-linked library for incorporation into other software programs. PMID:19603484
Fitmunk: improving protein structures by accurate, automatic modeling of side-chain conformations
Porebski, Przemyslaw Jerzy; Cymborowski, Marcin; Pasenkiewicz-Gierula, Marta; Minor, Wladek
Improvements in crystallographic hardware and software have allowed automated structure-solution pipelines to approach a near-'one-click' experience for the initial determination of macromolecular structures. However, in many cases the resulting initial model requires a laborious, iterative process of refinement and validation. A new method has been developed for the automatic modeling of side-chain conformations that takes advantage of rotamer-prediction methods in a crystallographic context. The algorithm, which is based on deterministic dead-end elimination (DEE) theory, uses new dense conformer libraries and a hybrid energy function derived from experimental data and prior information about rotamer frequencies to find the optimal conformation of each side chain. In contrast to existing methods, which incorporate the electron-density term into protein-modeling frameworks, the proposed algorithm is designed to take advantage of the highly discriminatory nature of electron-density maps. This method has been implemented in the program Fitmunk, which uses extensive conformational sampling. This improves the accuracy of the modeling and makes it a versatile tool for crystallographic model building, refinement and validation. Fitmunk was extensively tested on over 115 new structures, as well as a subset of 1100 structures from the PDB. It is demonstrated that the ability of Fitmunk to model more than 95% of side chains accurately is beneficial for improving the quality of crystallographic protein models, especially at medium and low resolutions. Fitmunk can be used for model validation of existing structures and as a tool to assess whether side chains are modeled optimally or could be better fitted into electron density. Fitmunk is available as a web service at http://kniahini.med.virginia.edu/fitmunk/server/ or at http://fitmunk.bitbucket.org/. PMID:26894674
Contribution of cutinase serine 42 side chain to the stabilization of the oxyanion transition state.
Nicolas, A; Egmond, M; Verrips, C T; de Vlieg, J; Longhi, S; Cambillau, C; Martinez, C
Cutinase from the fungus Fusarium solani pisi is a lipolytic enzyme able to hydrolyze both aggregated and soluble substrates. It therefore provides a powerful tool for probing the mechanisms underlying lipid hydrolysis. Lipolytic enzymes have a catalytic machinery similar to those present in serine proteinases. It is characterized by the triad Ser, His, and Asp (Glu) residues, by an oxyanion binding site that stabilizes the transition state via hydrogen bonds with two main chain amide groups, and possibly by other determinants. It has been suggested on the basis of a covalently bond inhibitor that the cutinase oxyanion hole may consist not only of two main chain amide groups but also of the Ser42 O gamma side chain. Among the esterases and the serine and the cysteine proteases, only Streptomyces scabies esterase, subtilisin, and papain, respectively, have a side chain residue which is involved in the oxyanion hole formation. The position of the cutinase Ser42 side chain is structurally conserved in Rhizomucor miehei lipase with Ser82 O gamma, in Rhizopus delemar lipase with Thr83 O gamma 1, and in Candida antartica B lipase with Thr40 O gamma 1. To evaluate the increase in the tetrahedral intermediate stability provided by Ser42 O gamma, we mutated Ser42 into Ala. Furthermore, since the proper orientation of Ser42 O gamma is directed by Asn84, we mutated Asn84 into Ala, Leu, Asp, and Trp, respectively, to investigate the contribution of this indirect interaction to the stabilization of the oxyanion hole. The S42A mutation resulted in a drastic decrease in the activity (450-fold) without significantly perturbing the three-dimensional structure. The N84A and N84L mutations had milder kinetic effects and did not disrupt the structure of the active site, whereas the N84W and N84D mutations abolished the enzymatic activity due to drastic steric and electrostatic effects, respectively. PMID:8555209
Rhamnoarabinosyl and rhamnoarabinoarabinosyl side chains as structural features of coffee arabinogalactans.
Nunes, Fernando M; Reis, Ana; Silva, Artur M S; Domingues, M Rosário M; Coimbra, Manuel A
The hot water soluble green coffee arabinogalactans, representing nearly 7% of total coffee bean arabinogalactans, were characterized by (1)H and (13)C NMR and, after partial acid hydrolysis, by ESI-MS/MS. Data obtained showed that these are highly branched type II arabinogalactans covalently linked to proteins (AGP), with a protein moiety containing 10% of 4-hydroxyproline residues. They possess a beta-(1-->3)-Galp/beta-(1-->3,6)-Galp ratio of 0.80, with a sugars composition of Rha:Ara:Gal of 0.25:1.0:1.5, and containing 2mol% of glucuronic acid residues. Beyond the occurrence of single alpha-L-Araf residues and [alpha-L-Araf-(1-->5)-alpha-L-Araf-(1-->] disaccharide residues as side chains, these AGPs contain unusual side chains at O-3 position of the beta-(1-->6)-linked galactopyranosyl residues composed by [alpha-L-Rhap-(1-->5)-alpha-L-Araf-(1-->] and [alpha-L-Rhap-(1-->5)-alpha-L-Araf-(1-->5)-alpha-L-Araf-(1-->] oligosaccharides. Rhamnoarabinosyl and rhamnoarabinoarabinosyl side chains are reported for the first time as structural features of plant arabinogalactan-proteins. PMID:18343467
Predicting side-chain conformations of methionine using a hard-sphere model with stereochemical constraints
NASA Astrophysics Data System (ADS)
Virrueta, A.; Gaines, J.; O'Hern, C. S.; Regan, L.
Current research in the O'Hern and Regan laboratories focuses on the development of hard-sphere models with stereochemical constraints for protein structure prediction as an alternative to molecular dynamics methods that utilize knowledge-based corrections in their force-fields. Beginning with simple hydrophobic dipeptides like valine, leucine, and isoleucine, we have shown that our model is able to reproduce the side-chain dihedral angle distributions derived from sets of high-resolution protein crystal structures. However, methionine remains an exception - our model yields a chi-3 side-chain dihedral angle distribution that is relatively uniform from 60 to 300 degrees, while the observed distribution displays peaks at 60, 180, and 300 degrees. Our goal is to resolve this discrepancy by considering clashes with neighboring residues, and averaging the reduced distribution of allowable methionine structures taken from a set of crystallized proteins. We will also re-evaluate the electron density maps from which these protein structures are derived to ensure that the methionines and their local environments are correctly modeled. This work will ultimately serve as a tool for computing side-chain entropy and protein stability. A. V. is supported by an NSF Graduate Research Fellowship and a Ford Foundation Fellowship. J. G. is supported by NIH training Grant NIH-5T15LM007056-28.
Side Chain Hydrophobicity Modulates Therapeutic Activity and Membrane Selectivity of Antimicrobial Peptide Mastoparan-X
Gjetting, Torben; Andresen, Thomas L.
The discovery of new anti-infective compounds is stagnating and multi-resistant bacteria continue to emerge, threatening to end the "antibiotic era". Antimicrobial peptides (AMPs) and lipo-peptides such as daptomycin offer themselves as a new potential class of antibiotics; however, further optimization is needed if AMPs are to find broad use as antibiotics. In the present work, eight analogues of mastoparan-X (MPX) were investigated, having side chain modifications in position 1, 8 and 14 to modulate peptide hydrophobicity. The self-association properties of the peptides were characterized, and the peptide-membrane interactions in model membranes were compared with the bactericidal and haemolytic properties. Alanine substitution at position 1 and 14 resulted in higher target selectivity (red blood cells versus bacteria), but also decreased bactericidal potency. For these analogues, the gain in target selectivity correlated to biophysical parameters showing an increased effective charge and reduction in the partitioning coefficient for membrane insertion. Introduction of an unnatural amino acid, with an octyl side chain by amino acid substitution, at positions 1, 8 and 14 resulted in increased bactericidal potency at the expense of radically reduced membrane target selectivity. Overall, optimized membrane selectivity or bactericidal potency was achieved by changes in side chain hydrophobicity of MPX. However, enhanced potency was achieved at the expense of selectivity and vice versa in all cases. PMID:24621994
Terahertz time domain and far-infrared spectroscopies of side-chain electro-optic polymers
NASA Astrophysics Data System (ADS)
Yamada, Toshiki; Kaji, Takahiro; Aoki, Isao; Yamada, Chiyumi; Mizuno, Maya; Saito, Shingo; Tominari, Yukihiro; Tanaka, Shukichi; Otomo, Akira
We investigated the dielectric properties of side-chain electro-optic polymers in a broad THz frequency region (90 GHz to 7 THz). For this investigation, we used terahertz time domain spectroscopy and the absorption coefficient in a broader frequency region of up to 20 THz that was obtained by far-infrared spectroscopy. The polymers studied were a new methacrylate polymer with a high-hyperpolarizability chromophore as the sidechain, a side-chain copolymer Disperse Red 1 polymethylmethacrylate, and pure polymethylmethacrylate. The dielectric properties in the low THz frequency region (∼0.1 THz) provide us with important information about the intrinsic refractive index for ultrahigh-speed electro-optic modulation (∼100 GHz), as well as versatile information such as the absorption coefficient and dielectric loss. The THz and far-infrared spectroscopic data in the wide frequency region provide us with the fundamental data for applications of side-chain electro-optic polymers within THz generation and detection.
Entropy and enthalpy of interaction between amino acid side chains in nanopores
Vaitheeswaran, S.; Thirumalai, D.
Understanding the stabilities of proteins in nanopores requires a quantitative description of confinement induced interactions between amino acid side chains. We use molecular dynamics simulations to study the nature of interactions between the side chain pairs ALA-PHE, SER-ASN, and LYS-GLU in bulk water and in water-filled nanopores. The temperature dependence of the bulk solvent potentials of mean force and the interaction free energies in cylindrical and spherical nanopores is used to identify the corresponding entropic and enthalpic components. The entropically stabilized hydrophobic interaction between ALA and PHE in bulk water is enthalpically dominated upon confinement depending on the relative orientations between the side chains. In the case of SER-ASN, hydrogen bonded configurations that are similar in bulk water are thermodynamically distinct in a cylindrical pore, thus making rotamer distributions different from those in the bulk. Remarkably, salt bridge formation between LYS-GLU is stabilized by entropy in contrast to the bulk. Implications of our findings for confinement-induced alterations in protein stability are briefly outlined.
Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly
Horne, W. Seth; Price, Joshua L.; Gellman, Samuel H.
The extent to which polypeptide conformation depends on side-chain composition and sequence has been widely studied, but less is known about the importance of maintaining an α-amino acid backbone. Here, we examine a series of peptides with backbones that feature different repeating patterns of α- and β-amino acid residues but an invariant side-chain sequence. In the pure α-backbone, this sequence corresponds to the previously studied peptide GCN4-pLI, which forms a very stable four-helix bundle quaternary structure. Physical characterization in solution and crystallographic structure determination show that a variety of α/β-peptide backbones can adopt sequence-encoded quaternary structures similar to that of the α prototype. There is a loss in helix bundle stability upon β-residue incorporation; however, stability of the quaternary structure is not a simple function of β-residue content. We find that cyclically constrained β-amino acid residues can stabilize the folds of α/β-peptide GCN4-pLI analogues and restore quaternary structure formation to backbones that are predominantly unfolded in the absence of cyclic residues. Our results show a surprising degree of plasticity in terms of the backbone compositions that can manifest the structural information encoded in a sequence of amino acid side chains. These findings offer a framework for the design of nonnatural oligomers that mimic the structural and functional properties of proteins. PMID:18587049
High-Performance Electron Acceptor with Thienyl Side Chains for Organic Photovoltaics.
Lin, Yuze; Zhao, Fuwen; He, Qiao; Huo, Lijun; Wu, Yang; Parker, Timothy C; Ma, Wei; Sun, Yanming; Wang, Chunru; Zhu, Daoben; Heeger, Alan J; Marder, Seth R; Zhan, Xiaowei
We develop an efficient fused-ring electron acceptor (ITIC-Th) based on indacenodithieno[3,2-b]thiophene core and thienyl side-chains for organic solar cells (OSCs). Relative to its counterpart with phenyl side-chains (ITIC), ITIC-Th shows lower energy levels (ITIC-Th: HOMO = -5.66 eV, LUMO = -3.93 eV; ITIC: HOMO = -5.48 eV, LUMO = -3.83 eV) due to the σ-inductive effect of thienyl side-chains, which can match with high-performance narrow-band-gap polymer donors and wide-band-gap polymer donors. ITIC-Th has higher electron mobility (6.1 × 10(-4) cm(2) V(-1) s(-1)) than ITIC (2.6 × 10(-4) cm(2) V(-1) s(-1)) due to enhanced intermolecular interaction induced by sulfur-sulfur interaction. We fabricate OSCs by blending ITIC-Th acceptor with two different low-band-gap and wide-band-gap polymer donors. In one case, a power conversion efficiency of 9.6% was observed, which rivals some of the highest efficiencies for single junction OSCs based on fullerene acceptors. PMID:27015115
Protein side-chain packing problem: a maximum edge-weight clique algorithmic approach.
Dukka Bahadur, K C; Tomita, Etsuji; Suzuki, Jun'ichi; Akutsu, Tatsuya
"Protein Side-chain Packing" has an ever-increasing application in the field of bio-informatics, dating from the early methods of homology modeling to protein design and to the protein docking. However, this problem is computationally known to be NP-hard. In this regard, we have developed a novel approach to solve this problem using the notion of a maximum edge-weight clique. Our approach is based on efficient reduction of protein side-chain packing problem to a graph and then solving the reduced graph to find the maximum clique by applying an efficient clique finding algorithm developed by our co-authors. Since our approach is based on deterministic algorithms in contrast to the various existing algorithms based on heuristic approaches, our algorithm guarantees of finding an optimal solution. We have tested this approach to predict the side-chain conformations of a set of proteins and have compared the results with other existing methods. We have found that our results are favorably comparable or better than the results produced by the existing methods. As our test set contains a protein of 494 residues, we have obtained considerable improvement in terms of size of the proteins and in terms of the efficiency and the accuracy of prediction. PMID:15751115
Mutations that replace aromatic side chains promote aggregation of the Alzheimer's Aβ peptide
Armstrong, Anne H.; Chen, Jermont; McKoy, Angela Fortner; Hecht, Michael H.
The aggregation of polypeptides into amyloid fibrils is associated with a number of human diseases. Because these fibrils – or intermediates on the aggregation pathway – play important roles in the etiology of disease, considerable effort has been expended to understand which features of the amino acid sequence promote aggregation. One feature suspected to direct aggregation is the π-stacking of aromatic residues. Such π-stacking interactions have also been proposed as the targets for various aromatic compounds that are known to inhibit aggregation. In the case of Alzheimer's disease, the aromatic side chains Phe19 and Phe20 in the wild-type amyloid beta (Aβ) peptide have been implicated. To explicitly test whether the aromaticity of these side chains plays a role in aggregation, we replaced these two phenylalanine side chains with leucines or isoleucines. These residues have similar sizes and hydrophobicities as Phe, but are not capable of π-stacking. Thioflavin-T fluorescence and electron microscopy demonstrate that replacement of residues 19 and 20 by Leu or Ile did not prevent aggregation, but rather enhanced amyloid formation. Further experiments showed that aromatic inhibitors of aggregation are as effective against Ile- and Leu-substituted versions of Aβ42 as they are against wild type Aβ. These results suggest that aromatic π-stacking interactions are not critical for Aβ aggregation or for the inhibition of Aβ aggregation. PMID:21513285
Synthesis of cyclic polyesters: effects of alkoxy side chains in salicylaldiminato tin(II) complexes.
Wongmahasirikun, Phonpimon; Prom-on, Paweenuch; Sangtrirutnugul, Preeyanuch; Kongsaeree, Palangpon; Phomphrai, Khamphee
A new class of salicylaldiminato tin(II) catalysts having different alkoxy side chains has been developed. The ligands were modified to have different lengths and flexibilities such as –(CH2)2– (2a), –(CH2)3– (2b), –(ortho-C6H4)CH2– (2c) and –(CH2)2–O–(CH2)2– (2d). Complexes 2a, b were characterized crystallographically revealing a more constrained environment around the metal in complex 2a. These catalysts are active for the solvent-free polymerization of L-lactide and ε-caprolactone. Complex 2a having a shorter side chain was shown to better promote intramolecular transesterification affording cyclic polylactides and cyclic poly(ε-caprolactone). Complexes 2b and 2d having longer side chains produced cyclic poly(ε-caprolactone) as a major product but failed to give cyclic polylactides. PMID:25757191
A new model for ligand release. Role of side chain in gating the enediyne antibiotic.
Hariharan, Parameswaran; Liang, Wenchuan; Chou, Shan-Ho; Chin, Der-Hang
Antitumor antibiotic chromoproteins such as neocarzinostatin involve a labile toxin that is tightly bound by a protective protein with very high affinity but must also be freed to exert its function. Contrary to the prevalent concept of ligand release, we established that toxin release from neocarzinostatin requires no major backbone conformational changes. We report, herein, that subtle changes in the side chains of specific amino acid residues are adequate to gate the release of chromophore. A recombinant wild type aponeocarzinostatin and its variants mutated around the opening of the chromophore binding cleft are employed to identify specific side chains likely to affect chromophore release. Preliminary, biophysical characterization of mutant apoproteins by circular dichroism and thermal denaturation indicate that the fundamental structural characteristics of wild type protein are conserved in these mutants. The chromophore reconstitution studies further show that all mutants are able to bind chromophore efficiently with similar complex structures. NMR studies on 15N-labeled mutants also suggest the intactness of binding pocket structure. Kinetic studies of chromophore release monitored by time course fluorescence and quantitative high pressure liquid chromatography analyses show that the ligand release rate is significantly enhanced only in Phe78 mutants. The extent of DNA cleavage in vitro corresponds well to the rate of chromophore release. The results provide the first clear-cut indication of how toxin release can be controlled by a specific side chain of a carrier protein. PMID:16567802
Enhanced docking with the mining minima optimizer: acceleration and side-chain flexibility.
Kairys, Visvaldas; Gilson, Michael K
The ligand-protein docking algorithm based on the Mining Minima method has been substantially enhanced. First, the basic algorithm is accelerated by: (1) adaptively determining the extent of each energy well to help avoid previously discovered energy minima; (2) biasing the search away from ligand positions at the surface of the receptor to prevent the ligand from staying at the surface when large sampling regions are used; (3) quickly testing multiple different ligand positions and orientations for each ligand conformation; and (4) tuning the source code to increase computational efficiency. These changes markedly shorten the time needed to discover an accurate result, especially when large sampling regions are used. The algorithm now also allows user-selected receptor sidechains to be treated as mobile during the docking procedure. The energies associated with the mobile side chains are computed as if they belonged to the ligand, except that atoms at the boundary between side chains and the rigid backbone are treated specially. This new capability is tested for several well-known ligand/protein systems, and preliminary application to an enzyme whose substrate is unknown--the recently solved hypothetical protein YecO (HI0319) from Haemophilus influenzae--indicates that side-chains relaxations allow candidate substrates of various sizes to be accommodated. PMID:12395431
Self-assembly of a series of random copolymers bearing amphiphilic side chains.
Wu, Xu; Qiao, Yingjie; Yang, Hui; Wang, Jinben
A novel series of comb-like random copolymers were prepared by polymerization of amphiphilic macromonomers, 2-(acrylamido)-octane sulfonic acid (AMC(8)S), 2-(acrylamido)-dodecane sulfonic acid (AMC(12)S), and 2-(acrylamido)-hexadecane sulfonic acid (AMC(16)S), with 2-(acrylamido)-2-methylpropanesulfonic acid (AMPS) respectively. The synthesis of the polymers with the same contents of amphiphilic units as side chains, but different chain length, enabled us to study the chain length dependence of their association in salt solution. Steady-state fluorescence measurements with pyrene as a polarity probe, quasielastic light scattering techniques (QELS) and transmission electron micrograph (TEM) were employed to investigate the associative properties of the system. The above investigations showed that all kinds of side chains begin to assemble at certain polymer concentrations and the critical aggregation concentration (CAC) decrease dramatically with the increase in the length and content of alkyl. An interesting phenomenon is that the assembly tends more favorably to occur among different molecules rather than within single molecule when the number of carbon atoms in the alkyl groups or the polymer concentration increases, leading to the formation of larger multimolecular micelle-like aggregate. The aim of the present work is to establish the fundamental preconditions of intramolecular and intermolecular association fashions for the polymers, which is useful for the exploitation of functional groups and contributes to the development of amphiphilic random polymers. PMID:20576273
Molecular structure and rheological properties of short-side-chain heavily glycosylated porcine stomach mucin.
Yakubov, Gleb E; Papagiannopoulos, Aristeidis; Rat, Elodie; Easton, Richard L; Waigh, Thomas A
The current accepted model for high-molecular-weight gastric mucins of the MUC family is that they adopt a polydisperse coil conformation in bulk solutions. We develop this model using well-characterized highly purified porcine gastric mucin Orthana that is genetically close to the human MUC6 type. It has short side chains and low levels of sialic acid residues and includes minute amounts of cysteine residues that, if abundant, can be responsible for the self-polymerization of mucin. We have established that the mucin structure in bulk solutions corresponds to a daisy-chain random coil. Dynamic light scattering experiments probe the internal dynamics of globular subunits (individual daisies) at the approximately 9 nm length scale, whereas viscosity and light scattering measurements indicate that the size of the whole mucin chains is much larger, approximately 50 nm. The bulk viscosity (eta) scales with mucin concentration (c) in a manner similar to that found for short-side-chain synthetic comb polyelectrolytes and is characterized by a transition between semidilute (eta approximately c1/2) and entangled (eta approximately c3/2) regimes. PMID:17910495
Novel endomorphin-1 analogs with C-terminal oligoarginine-conjugation display systemic antinociceptive activity with less gastrointestinal side effects.
Wang, Chang-lin; Qiu, Ting-ting; Diao, Yu-xiang; Zhang, Yao; Gu, Ning
In recent study, in order to improve the bioavailability of endomorphin-1 (EM-1), we designed and synthesized a series of novel EM-1 analogs by replacement of L-Pro(2) by β-Pro, D-Ala or Sar, together with C-terminal oligoarginine-conjugation. Our results indicated that the introduction of D-Ala and β-Pro in position 2, along with oligoarginine-conjugation, didn't significantly decrease the μ-affinity and in vitro bioactivity, and the enhancement of arginine residues did not markedly influence the μ-affinity of these analogs. All analogs displayed a significant enhancement of stability, which may be due to increased resistance to proline-specific enzymatic degradation. Moreover, following intracerebroventricular (i.c.v.) administration, analogs 1, 2, 4 and 5 produced significant antinociception and increased duration of action, with the ED50 values being about 1.8- to 4.2-fold less potent than that of EM-1. In addition, our results indicated that no significant antinociceptive activity of EM-1 was seen following subcutaneous (s.c.) injection, whereas analogs 1, 2, 4 and 5 with equimolar dose induced significant and prolonged antinociception by an opioid and central mechanism. Herein, we further examined the gastrointestinal transit and colonic propulsive latencies of EM-1 and its four analogs administered centrally and peripherally. I.c.v. administration of EM-1 and analogs 1, 2, 4 and 5 significantly delayed gastrointestinal transit and colonic bead propulsion in mice, but the inhibitory effects induced by these analogs were largely attenuated. It is noteworthy that no significant gastrointestinal side effects induced by these four analogs were observed after s.c. administration. Our results demonstrated that combined modifications of EM-1 with unnatural amino acid substitutions and oligoarginine-conjugation gave an efficient strategy to improve the analgesic profile of EM-1 analogs but with less gastrointestinal side effects when administered peripherally
Actinobacterial Acyl Coenzyme A Synthetases Involved in Steroid Side-Chain Catabolism
Casabon, Israël; Swain, Kendra; Crowe, Adam M.
Bacterial steroid catabolism is an important component of the global carbon cycle and has applications in drug synthesis. Pathways for this catabolism involve multiple acyl coenzyme A (CoA) synthetases, which activate alkanoate substituents for β-oxidation. The functions of these synthetases are poorly understood. We enzymatically characterized four distinct acyl-CoA synthetases from the cholate catabolic pathway of Rhodococcus jostii RHA1 and the cholesterol catabolic pathway of Mycobacterium tuberculosis. Phylogenetic analysis of 70 acyl-CoA synthetases predicted to be involved in steroid metabolism revealed that the characterized synthetases each represent an orthologous class with a distinct function in steroid side-chain degradation. The synthetases were specific for the length of alkanoate substituent. FadD19 from M. tuberculosis H37Rv (FadD19Mtb) transformed 3-oxo-4-cholesten-26-oate (kcat/Km = 0.33 × 105 ± 0.03 × 105 M−1 s−1) and represents orthologs that activate the C8 side chain of cholesterol. Both CasGRHA1 and FadD17Mtb are steroid-24-oyl-CoA synthetases. CasG and its orthologs activate the C5 side chain of cholate, while FadD17 and its orthologs appear to activate the C5 side chain of one or more cholesterol metabolites. CasIRHA1 is a steroid-22-oyl-CoA synthetase, representing orthologs that activate metabolites with a C3 side chain, which accumulate during cholate catabolism. CasI had similar apparent specificities for substrates with intact or extensively degraded steroid nuclei, exemplified by 3-oxo-23,24-bisnorchol-4-en-22-oate and 1β(2′-propanoate)-3aα-H-4α(3″-propanoate)-7aβ-methylhexahydro-5-indanone (kcat/Km = 2.4 × 105 ± 0.1 × 105 M−1 s−1 and 3.2 × 105 ± 0.3 × 105 M−1 s−1, respectively). Acyl-CoA synthetase classes involved in cholate catabolism were found in both Actinobacteria and Proteobacteria. Overall, this study provides insight into the physiological roles of acyl-CoA synthetases in steroid catabolism and
Conjugated processes of the chemical transformation of sulfur dioxide under the effect of chain gas-phase reactions
NASA Astrophysics Data System (ADS)
Mantashyan, A. A.
The effect sulfur dioxide has on the dynamics of the spontaneous ignition of hydrogen-oxygen mixtures is studied. Additives of SO2 have no negative effect on spontaneous ignition and undergo chemical conversion to form elemental sulfur. The results are analyzed using the theory of branched chain reactions along with data on SO2 conversion under the action of chain reactions of hydrocarbon oxidation and slow hydrogen oxidation. The transformations classified as parallel reactions from the viewpoint of formal kinetics could actually be conjugated radical-chain processes.
Anti-hepatoma human single-chain Fv antibody and adriamycin conjugates with potent antitumor activity.
Chen, Lin; Liu, Yan-Hong; Li, Yue-Hui; Jiang, Yan; Xie, Ping-Li; Zhou, Guo-Hua; Li, Guan-Cheng
To construct an improved biological missile, an immunoconjugate ADM-Dex-ScFv-SA3 was synthesized, which was composed of a hepatocellular carcinoma-specific, single-chain Fv antibody (ScFv-SA3) and a highly potent cytotoxic drug, adriamycin (ADM), as the warhead. Oxidized Dextran T10 (Dex-T10) was used as a linker to connect these two moieties. The 40 KD soluble anti-hepatoma human Trx-ScFv-SA3 protein was expressed in E. coli BL21 (DE3), using a prokaryotic expression vector, pET21a (+)-Trx-ScFv-SA3-His. It was purified using a His-Tag Ni-Agarose column and identified by western blot. The activity of Trx-ScFv-SA3 was verified by enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry to confirm that it specifically binds to the hepatocellular carcinoma cell line HepG2. To prepare ADM-Dex-ScFv-SA3, ADM was conjugated to the antibody at a molar ratio of 14.21:1. The antitumor effect of the conjugate was tested by MTT assay, plate colony formation assay and xenografts in a nude mice experimental model. In vitro experiments revealed that ADM-Dex-ScFv-SA3 could bind to tumor cells selectively and inhibit the proliferation and the colony formation ability of HepG2 cells. In vivo experiments showed that ADM-Dex-ScFv-SA3 suppressed the tumor growth and prolonged the median survival time in tumor-bearing mice. Tumor histology slides indicated a significantly slower tumor tissue proliferation in the ADM-Dex-ScFv-SA3 group. These data indicate that the targeted drug, ADM-Dex-ScFv-SA3, may be a highly potent and selective therapy for the treatment of hepatoma. PMID:24239629
Improvement in the Thermal Stability of Pyrophosphatase by Conjugation to Poly(N-isopropylacrylamide): Application to the Polymerase Chain Reaction.
Cui, Yuecheng; Liu, Feng; Li, Xin; Wang, Lei; Wang, Hongwei; Chen, Gaojian; Yuan, Lin; Brash, John L; Chen, Hong
Polymerase chain reaction (PCR) is a powerful method for nucleic acid amplification. However, the PCR is inhibited in its yield due to its byproduct, pyrophosphate (PPi), a byproduct of the reaction; the yield is thereby limited. The conventional method for hydrolysis of PPi by pyrophosphatase (PPase) is not well adapted for operation at elevated temperatures over long times as required during the PCR. In this work, we reported a strategy to improve the PCR yield using a conjugate of the enzyme with the thermally responsive polymer poly(N-isopropylacrylamide) (PNIPAM). Pyrophosphatase (PPase) was conjugated to PNIPAM site-specifically near the active center. As compared to the free enzyme, the optimum temperature of the conjugate was shown to increase from 45 to 60 °C. For the conjugate, about 77% enzyme activity was retained after incubation at 60 °C for 3 h, representing a 6.8-fold increase as compared to the unconjugated enzyme. For the PCR using the conjugate, the yield was 1.5-fold greater than using the unconjugated enzyme. As well as improving the yield of the PCR (and possibly other biological reactions) at elevated temperature, polymer conjugation may also provide a strategy to improve the heat resistance of proteins more generally. PMID:26373436
Side-chain recognition and gating in the ribosome exit tunnel
Petrone, Paula M.; Snow, Christopher D.; Lucent, Del; Pande, Vijay S.
The ribosome is a large complex catalyst responsible for the synthesis of new proteins, an essential function for life. New proteins emerge from the ribosome through an exit tunnel as nascent polypeptide chains. Recent findings indicate that tunnel interactions with the nascent polypeptide chain might be relevant for the regulation of translation. However, the specific ribosomal structural features that mediate this process are unknown. Performing molecular dynamics simulations, we are studying the interactions between components of the ribosome exit tunnel and different chemical probes (specifically different amino acid side chains or monovalent inorganic ions). Our free-energy maps describe the physicochemical environment of the tunnel, revealing binding crevices and free-energy barriers for single amino acids and ions. Our simulations indicate that transport out of the tunnel could be different for diverse amino acid species. In addition, our results predict a notable protein–RNA interaction between a flexible 23S rRNA tetraloop (gate) and ribosomal protein L39 (latch) that could potentially obstruct the tunnel's exit. By relating our simulation data to earlier biochemical studies, we propose that ribosomal features at the exit of the tunnel can play a role in the regulation of nascent chain exit and ion flux. Moreover, our free-energy maps may provide a context for interpreting sequence-dependent nascent chain phenomenology. PMID:18946046
Molecular dynamics studies of side chain effect on the beta-1,3-D-glucan triple helix in aqueous solution.
Okobira, Tadashi; Miyoshi, Kentaro; Uezu, Kazuya; Sakurai, Kazuo; Shinkai, Seiji
beta-1,3-D-glucans have been isolated from fungi as right-handed 6(1) triple helices. They are categorized by the side chains bound to the main triple helix through beta-(1-->6)-D-glycosyl linkage. Indeed, since a glucose-based side chain is water soluble, the presence and frequency of glucose-based side chains give rise to significant variation in the physical properties of the glucan family. Curdlan has no side chains and self-assembles to form an water-insoluble triple helical structure, while schizophyllan, which has a 1,6-D-glucose side chain on every third glucose unit along the main chain, is completely water soluble. A thermal fluctuation in the optical rotatory dispersion is observed for the side chain, indicating probable co-operative interaction between the side chains and water molecules. This paper documents molecular dynamics simulations in aqueous solution for three models of the beta-1,3-D-glucan series: curdlan (no side chain), schizophyllan (a beta-(1-->6)-D-glycosyl side-chain at every third position), and a hypothetical triple helix with a side chain at every sixth main-chain glucose unit. A decrease was observed in the helical pitch as the population of the side chain increased. Two types of hydrogen bonding via water molecules, the side chain/main chain and the side chain/side chain hydrogen bonding, play an important role in determination of the triple helix conformation. The formation of a one-dimensional cavity of diameter about 3.5 A was observed in the schizophyllan triple helix, while curdlan showed no such cavity. The side chain/side chain hydrogen bonding in schizophyllan and the hypothetical beta-1,3-D-glucan triple helix could cause the tilt of the main-chain glucose residues to the helix. PMID:18257529
Impact of nuclear lattice relaxation on the excitation energy transfer along a chain of π -conjugated molecules
NASA Astrophysics Data System (ADS)
Schmid, S. A.; Abbel, R.; Schenning, A. P. H. J.; Meijer, E. W.; Herz, L. M.
We have investigated the extent to which delocalization of the ground-state and excited-state wave functions of a π -conjugated molecule affects the excitation energy transfer (EET) between such molecules. Using femtosecond photoluminescence spectroscopy, we experimentally monitored the EET along well-defined supramolecular chains of extended conjugated molecules. Comparison with Monte Carlo simulations reveals that only a model incorporating a localized emitter and delocalized absorber wave function accurately reproduces these data. Our findings demonstrate that self-localization of the initially excited state, following fast relaxation of the nuclear lattice, has a significant impact on the EET dynamics in molecular assemblies.
Effect of side-chain asymmetry on the intermolecular structure and order-disorder transition in alkyl-substituted polyfluorenes
NASA Astrophysics Data System (ADS)
Knaapila, M.; Stepanyan, R.; Torkkeli, M.; Haase, D.; Fröhlich, N.; Helfer, A.; Forster, M.; Scherf, U.
We study relations among the side-chain asymmetry, structure, and order-disorder transition (ODT) in hairy-rod-type poly(9,9-dihexylfluorene) (PF6) with two identical side chains and atactic poly(9-octyl-9-methyl-fluorene) (PF1-8) with two different side chains per repeat. PF6 and PF1-8 organize into alternating side-chain and backbone layers that transform into an isotropic phase at TODT(PF 6 ) and TbiODT(PF 1 -8 ) . We interpret polymers in terms of monodisperse and bidisperse brushes and predict scenarios TODT
Theory of microphase separation on side-chain liquid-crystalline polymers with flexible spacers.
Hernández-Jiménez, M; Westfahl, H
We model a melt of monodisperse side-chain liquid-crystalline polymers as a melt of comb copolymers in which the side groups are rod-coil diblock copolymers. We consider both excluded-volume and Maier-Saupe interactions. The first acts among any pair of segments while the latter acts only between rods. Using a free-energy functional calculated from this microscopic model, we study the spinodal stability of the isotropic phase against density and orientational fluctuations. The phase diagram obtained in this way predicts nematic and smectic instabilities as well as the existence of microphases or phases with modulated wave vector but without nematic ordering. Such microphases are the result of the competition between the incompatibility among the blocks and the connectivity constraints imposed by the spacer and the backbone. Also the effects of the polymerization degree and structural conformation of the monomeric units on the phase behavior of the side-chain liquid-crystalline polymers are studied. PMID:17541501
Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains.
Winn, M; Arendsen, D; Dodge, P; Dren, A; Dunnigan, D; Hallas, R; Hwang, K; Kyncl, J; Lee, Y H; Plotnikoff, N; Young, P; Zaugg, H
Ten new delta6a,10a-THC analogs with arylalkyl side chains, one with a dimethylaminoalkyl side chain, and six heterocyclic delta6a,10a-THC analogs [8-substituted 5,5-dimethyl-10-hydroxy-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzo-pyrano[4,3-c]pyridines] were prepared. They showed pharmacological activity as analgesics, tranquilizers, antihypertensives, and hypnotics and as antisecretory, antiulcer, and antidiarrheal agents. The most potent compounds had either a 1-methyl-4-(4-fluorophenyl)butyl or a 1,2-dimethyl-4-(4-fluorophenyl)butyl side chain. PMID:817021
Unexpected side products in the conjugation of an amine-derivatized morpholino oligomer with p-isothiocyanate benzyl DTPA and their removal.
Liu, Guozheng; Dou, Shuping; Liu, Yuxia; Liang, Minmin; Chen, Ling; Cheng, Dengfeng; Greiner, Dale; Rusckowski, Mary; Hnatowich, Donald J
In connection with pretargeting, an amine-derivatized morpholino phosphorodiamidate oligomer (NH(2)-cMORF) was conjugated conventionally with p-isothiocyanate benzyl-DTPA (p-SCN-Bn-DTPA). However, after (111)In radiolabeling, unexpected label instability was observed. To understand this instability, the NH(2)-cMORF and, as control, the native cMORF without the amine were conjugated in the conventional manner. Surprisingly, the (111)In labeling of the native cMORF conjugate was equally effective as that of the NH(2)-cMORF conjugate (>95%) despite the absence of the amine group. Furthermore, heating the radiolabeled NH(2)-cMORF and native cMORF conjugates resulted in a 35% loss and a complete loss of the label, respectively. Since the (111)In labeled DTPA is known to be stable, the instability in both cases must be due to some unstable association of DTPA to the cMORF, presumably unstable association to some endogenous sites in cMORF. Based on this assumption, a postconjugation-prepurification heating step was introduced, and labeling efficiency and stability were again investigated. By introducing the heating step, the side products were dissociated, and after purification and labeling, the NH(2)-cMORF conjugate provided a stable label and high labeling efficiency with no need for postlabeling purification. The biodistribution of this radiolabeled conjugate in normal mice showed significantly lower backgrounds compared with the labeled unstable native cMORF conjugate. In conclusion, the conventional conjugation procedure to attach the p-SCN-Bn-DTPA to NH(2)-cMORF resulted in side product(s) that were responsible for the (111)In label instability. Adding a postconjugation-prepurification heating step dissociated the side products, improved the label stability and lowered tissue backgrounds in mice. PMID:21315270
Impact of charge carrier injection on single-chain photophysics of conjugated polymers
NASA Astrophysics Data System (ADS)
Hofmann, Felix J.; Vogelsang, Jan; Lupton, John M.
Charges in conjugated polymer materials have a strong impact on the photophysics and their interaction with the primary excited state species has to be taken into account in understanding device properties. Here, we employ single-molecule spectroscopy to unravel the influence of charges on several photoluminescence (PL) observables. The charges are injected either stochastically by a photochemical process or deterministically in a hole-injection sandwich device configuration. We find that upon charge injection, besides a blue-shift of the PL emission and a shortening of the PL lifetime due to quenching and blocking of the lowest-energy chromophores, the non-classical photon arrival time distribution of the multichromophoric chain is modified towards a more classical distribution. Surprisingly, the fidelity of photon antibunching deteriorates upon charging, whereas one would actually expect the opposite: the number of chromophores to be reduced. A qualitative model is presented to explain the observed PL changes. The results are of interest to developing a microscopic understanding of the intrinsic charge-exciton quenching interaction in devices.
Single molecule spectroscopy of conjugated polymer chains in an electric field-aligned liquid crystal.
Chang, Wei-Shun; Link, Stephan; Yethiraj, Arun; Barbara, Paul F
Using single molecule polarization spectroscopy, we investigated the alignment of a polymer solute with respect to the liquid crystal (LC) director in an LC device while applying an external electric field. The polymer solute is poly[2-methoxy-5-(2'-ethyl-hexyloxy)-1,4-phenylene vinylene] (or MEH-PPV), and the LC solvent is 5CB. The electric field induces a change in the LC director orientation from a planar alignment (no electric field) to a perpendicular (homeotropic) alignment with an applied field of 5.5 x 103 V/cm. We find that the polymer chains align with the LC director in both planar and homeotropic alignment when measured in the bulk of the LC solution away from the device interface. Single molecule polarization distributions measured as a function of distance from the LC device interface reveal a continuous change of the MEH-PPV alignment from planar to homeotropic. The observed polarization distributions are modeled using a conventional elastic model that predicts the depth profile of the LC director orientation for the applied electric field. The excellent agreement between experiment and simulations shows that the alignment of MEH-PPV follows the LC director throughout the LC sample. Furthermore, our results suggest that conjugated polymers such as MEH-PPV can be used as sensitive local probes to explore complex (and unknown) structures in anisotropic media. PMID:17975912
A Bayesian Approach for Determining Protein Side-Chain Rotamer Conformations Using Unassigned NOE Data
Zeng, Jianyang; Roberts, Kyle E.; Zhou, Pei
Abstract A major bottleneck in protein structure determination via nuclear magnetic resonance (NMR) is the lengthy and laborious process of assigning resonances and nuclear Overhauser effect (NOE) cross peaks. Recent studies have shown that accurate backbone folds can be determined using sparse NMR data, such as residual dipolar couplings (RDCs) or backbone chemical shifts. This opens a question of whether we can also determine the accurate protein side-chain conformations using sparse or unassigned NMR data. We attack this question by using unassigned nuclear Overhauser effect spectroscopy (NOESY) data, which records the through-space dipolar interactions between protons nearby in three-dimensional (3D) space. We propose a Bayesian approach with a Markov random field (MRF) model to integrate the likelihood function derived from observed experimental data, with prior information (i.e., empirical molecular mechanics energies) about the protein structures. We unify the side-chain structure prediction problem with the side-chain structure determination problem using unassigned NMR data, and apply the deterministic dead-end elimination (DEE) and A* search algorithms to provably find the global optimum solution that maximizes the posterior probability. We employ a Hausdorff-based measure to derive the likelihood of a rotamer or a pairwise rotamer interaction from unassigned NOESY data. In addition, we apply a systematic and rigorous approach to estimate the experimental noise in NMR data, which also determines the weighting factor of the data term in the scoring function derived from the Bayesian framework. We tested our approach on real NMR data of three proteins: the FF Domain 2 of human transcription elongation factor CA150 (FF2), the B1 domain of Protein G (GB1), and human ubiquitin. The promising results indicate that our algorithm can be applied in high-resolution protein structure determination. Since our approach does not require any NOE assignment, it can
A Bayesian Approach for Determining Protein Side-Chain Rotamer Conformations Using Unassigned NOE Data
NASA Astrophysics Data System (ADS)
Zeng, Jianyang; Roberts, Kyle E.; Zhou, Pei; Donald, Bruce R.
A major bottleneck in protein structure determination via nuclear magnetic resonance (NMR) is the lengthy and laborious process of assigning resonances and nuclear Overhauser effect (NOE) cross peaks. Recent studies have shown that accurate backbone folds can be determined using sparse NMR data, such as residual dipolar couplings (RDCs) or backbone chemical shifts. This opens a question of whether we can also determine the accurate protein side-chain conformations using sparse or unassigned NMR data. We attack this question by using unassigned nuclear Overhauser effect spectroscopy (NOESY) data, which record the through-space dipolar interactions between protons nearby in 3D space. We propose a Bayesian approach with a Markov random field (MRF) model to integrate the likelihood function derived from observed experimental data, with prior information (i.e., empirical molecular mechanics energies) about the protein structures. We unify the side-chain structure prediction problem with the side-chain structure determination problem using unassigned NMR data, and apply the deterministic dead-end elimination (DEE) and A* search algorithms to provably find the global optimum solution that maximizes the posterior probability. We employ a Hausdorff-based measure to derive the likelihood of a rotamer or a pairwise rotamer interaction from unassigned NOESY data. In addition, we apply a systematic and rigorous approach to estimate the experimental noise in NMR data, which also determines the weighting factor of the data term in the scoring function that is derived from the Bayesian framework. We tested our approach on real NMR data of three proteins, including the FF Domain 2 of human transcription elongation factor CA150 (FF2), the B1 domain of Protein G (GB1), and human ubiquitin. The promising results indicate that our approach can be applied in high-resolution protein structure determination. Since our approach does not require any NOE assignment, it can accelerate the NMR
MCCE2: Improving Protein pKa Calculations with Extensive Side Chain Rotamer Sampling
Multiconformation continuum electrostatics (MCCE) explores different conformational degrees of freedom in Monte Carlo calculations of protein residue and ligand pKas. Explicit changes in side chain conformations throughout a titration create a position dependent, heterogeneous dielectric response giving a more accurate picture of coupled ionization and position changes. The MCCE2 methods for choosing a group of input heavy atom and proton positions are described. The pKas calculated with different isosteric conformers, heavy atom rotamers and proton positions, with different degrees of optimization are tested against a curated group of 305 experimental pKas in 33 proteins. QUICK calculations, with rotation around Asn and Gln termini, sampling His tautomers and torsion minimum hydroxyls yield an RMSD of 1.34 with 84% of the errors being <1.5 pH units. FULL calculations adding heavy atom rotamers and side chain optimization yield an RMSD of 0.90 with 90% of the errors <1.5 pH unit. Good results are also found for pKas in the membrane protein bacteriorhodopsin. The inclusion of extra side chain positions distorts the dielectric boundary and also biases the calculated pKas by creating more neutral than ionized conformers. Methods for correcting these errors are introduced. Calculations are compared with multiple X-ray and NMR derived structures in 36 soluble proteins. Calculations with X-ray structures give significantly better pKas. Results with the default protein dielectric constant of 4 are as good as those using a value of 8. PMID:19274707
Proline-glutamate chimera's side chain conformation directs the type of β-hairpin structure.
Maity, Jyotirmoy; Gerling, Ulla I M; Vukelić, Stella; Schäfer, Andreas; Koksch, Beate
Our aim was to study the impact of two proline chimeras, containing a glutamic acid side chain in cis- or trans-configuration, on secondary structure formation. We further investigated to what extent the configuration of the side chain contributes to the overall peptide conformation. We used a 10 residue peptide (IYSNPDGTWT) that forms a β-hairpin in water. The turn-forming proline was substituted with either a cis- or trans-proline-glutamic acid chimera, resulting in the peptides IYSNPcis -E DGTWT (P1_Pcis-E) and IYSNP(trans-E)DGTWT (P1_Ptrans-E). We studied the conformation of the modified peptides by circular dichroism (CD) and NMR-spectroscopy, and SEC/static light scattering (SLS) analysis. NMR analysis reveals that the modified peptides maintain the β-hairpin conformation in aqueous solution. At 5 °C and pH 4.3, the peptide (P1_Pcis-E) was found to adopt two coexisting β-hairpin conformations (2:2 β-hairpin, and 3:5 β-hairpin). In contrast to that, the peptide (P1_Ptrans-E) adopts a 2:2 β-hairpin that exists in equilibrium with a 4:4 β-hairpin conformation. The adoption of ordered β-hairpin structures for both modified peptides could be confirmed by CD spectroscopy, while SEC/SLS analysis showed a monomeric oligomerization state for all three investigated peptides. With the combination of several NMR methods, we were able to elucidate that even small alterations in the side chain conformation of the proline-glutamate chimera (cis or trans) can significantly influence the conformation of the adopted β-hairpin. PMID:24221353
Solubility control of regioregular 3-substituted polythiophenes bearing 2-phenylnaphthalene side chain by copolymerisation
NASA Astrophysics Data System (ADS)
Watanabe, Mari; Kijima, Masashi
Two types of 2,5-dibromothiophene monomers having a dodecyl chain and a 2-phenylnaphthalene one were randomly copolymerised in different feed molar ratio by Ni-catalysed chain-growth polymerisation method. Regioregularity of all polymers were sufficiently high (88-97%). Absorption λmax due to π-π* transition of polythiophene backbones in solutions were observed at 444-451 nm for all polymers, which were almost similar to each other and typical of the optical characteristics of regioregular poly(3-alkylthiophene)s. The homopolymer of the latter monomer that had the phenylnaphthalene side group showed poor solubility to common organic solvents, i.e., it was insoluble in chloroform at room temperature and could dissolve only in hot solvents above 100 °C. The copolymers, which had higher number average molecular weights (Mn), had better solubility than that of the homopolymer.
Revealing the supramolecular nature of side-chain terpyridine-functionalized polymer networks.
Brassinne, Jérémy; Jochum, Florian D; Fustin, Charles-André; Gohy, Jean-François
Nowadays, finely controlling the mechanical properties of polymeric materials is possible by incorporating supramolecular motifs into their architecture. In this context, the synthesis of a side-chain terpyridine-functionalized poly(2-(dimethylamino)ethyl methacrylate) is reported via reversible addition-fragmentation chain transfer polymerization. By addition of transition metal ions, concentrated aqueous solutions of this polymer turn into metallo-supramolecular hydrogels whose dynamic mechanical properties are investigated by rotational rheometry. Hence, the possibility for the material to relax mechanical constrains via dissociation of transient cross-links is brought into light. In addition, the complex phenomena occurring under large oscillatory shear are interpreted in the context of transient networks. PMID:25569082
Alpha-helical stabilization by side chain shielding of backbone hydrogen bonds.
García, Angel E; Sanbonmatsu, Kevin Y
We study atomic models of the thermodynamics of the structural transition of peptides that form alpha-helices. The effect of sequence variation on alpha-helix formation for alanine-rich peptides, Ac-Ala21-methyl amide (A21) and Ac-A5 (AAARA)3A-methyl amide (Fs peptide), is investigated by atomic simulation studies of the thermodynamics of the helix-coil transition in explicit water. The simulations show that the guanidinium group in the Arg side chains in the Fs peptide interacts with the carbonyl group four amino acids upstream in the chain and desolvates backbone hydrogen bonds. This desolvation can be directly correlated with a higher probability of hydrogen bond formation. We find that Fs has higher helical content than A21 at all temperatures. A small modification in the amber force field reproduces the experimental helical content and helix-coil transition temperatures for the Fs peptide. PMID:11867710
Revealing the Supramolecular Nature of Side-Chain Terpyridine-Functionalized Polymer Networks
Brassinne, Jérémy; Jochum, Florian D.; Fustin, Charles-André; Gohy, Jean-François
Nowadays, finely controlling the mechanical properties of polymeric materials is possible by incorporating supramolecular motifs into their architecture. In this context, the synthesis of a side-chain terpyridine-functionalized poly(2-(dimethylamino)ethyl methacrylate) is reported via reversible addition-fragmentation chain transfer polymerization. By addition of transition metal ions, concentrated aqueous solutions of this polymer turn into metallo-supramolecular hydrogels whose dynamic mechanical properties are investigated by rotational rheometry. Hence, the possibility for the material to relax mechanical constrains via dissociation of transient cross-links is brought into light. In addition, the complex phenomena occurring under large oscillatory shear are interpreted in the context of transient networks. PMID:25569082
Improving the reactivity of phenylacetylene macrocycles toward topochemical polymerization by side chains modification
Daigle, Maxime; Cantin, Katy
Summary The synthesis and self-assembly of two new phenylacetylene macrocycle (PAM) organogelators were performed. Polar 2-hydroxyethoxy side chains were incorporated in the inner part of the macrocycles to modify the assembly mode in the gel state. With this modification, it was possible to increase the reactivity of the macrocycles in the xerogel state to form polydiacetylenes (PDAs), leading to a significant enhancement of the polymerization yields. The organogels and the PDAs were characterized using Raman spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM). PMID:25161718
Dendrocyin: an isocucurbitacin with novel cyclic side chain from Dendrosicyos socotrana.
Hussein, Hosny A; Abdel-Halim, Osama B; Marwan, El-Sayed M; El-Gamal, Ali A; Mosana, Ramazy
Dendrosicyos socotrana Balf.f. is a unique species (Cucurbitaceae) native to Socotra island in the horn of Africa. From the chloroform extract of the stems, A new isocucurbitacin (Dendrocyin) with unusual cyclization in the side chain; 24beta-ethoxy-20-25-epoxy-3alpha,16alpha-dihydroxy-9-methyl-19-norlanost-5(6) ene-2,11,22-trione has been isolated alongside isocucurbitacin R. Their structural configuration were established by usual spectroscopic (1H NMR, 13C NMR and DEPT) and two-dimensional NMR techniques (1H-1H Cosy, HMBC and HMQC). PMID:15451315
Cyclic side-chain phenylazo naphthalene polymers: enhanced fluorescence emission and surface relief grating formation.
Zhang, Hao; Zhou, Nianchen; Zhu, Xing; Chen, Xinrong; Zhang, Zhengbiao; Zhang, Wei; Zhu, Jian; Hu, Zhijun; Zhu, Xiulin
Well-defined cyclic-polymers (cyclic-PAzoMMAs), bearing side-chain phenylazo naphthalene chromophore, were successfully synthesized by the combination of atom transfer radical polymerization (ATRP) and copper(I)-catalyzed azide/alkyne cycloaddition "click" reaction, as verified by GPC, (1) H NMR, FTIR, and MALDI-TOF mass spectrometry. The cyclic-PAzoMMA showed higher glass transition temperatures than the linear-PAzoMMA with the same molecular weight. Interestingly, the cyclic-PAzoMMA exhibited deeper modulation depth (M.D.) induced by SRG, larger value of the photoinduced birefringence, increased fluorescence emission, and longer fluorescence lifetime in comparison with its linear counterpart. PMID:22965741
Recent advances in metathesis-derived polymers containing transition metals in the side chain.
Dragutan, Ileana; Dragutan, Valerian; Simionescu, Bogdan C; Demonceau, Albert; Fischer, Helmut
This account critically surveys the field of side-chain transition metal-containing polymers as prepared by controlled living ring-opening metathesis polymerization (ROMP) of the respective metal-incorporating monomers. Ferrocene- and other metallocene-modified polymers, macromolecules including metal-carbonyl complexes, polymers tethering early or late transition metal complexes, etc. are herein discussed. Recent advances in the design and syntheses reported mainly during the last three years are highlighted, with special emphasis on new trends for superior applications of these hybrid materials. PMID:26877797
Recent advances in metathesis-derived polymers containing transition metals in the side chain
Demonceau, Albert; Fischer, Helmut
Summary This account critically surveys the field of side-chain transition metal-containing polymers as prepared by controlled living ring-opening metathesis polymerization (ROMP) of the respective metal-incorporating monomers. Ferrocene- and other metallocene-modified polymers, macromolecules including metal-carbonyl complexes, polymers tethering early or late transition metal complexes, etc. are herein discussed. Recent advances in the design and syntheses reported mainly during the last three years are highlighted, with special emphasis on new trends for superior applications of these hybrid materials. PMID:26877797
The Frozen State in the Liquid Phase of Side-Chain Liquid-Crystal Polymers
NASA Astrophysics Data System (ADS)
Mendil, H.; Noirez, L.; Baroni, P.; Grillo, I.
Quenched isotropic melts of side-chain liquid-crystal polymers reveal surprisingly an anisotropic polymer conformation. This small-angle neutron-scattering (SANS) result is consistent with the identification of a macroscopic, solidlike response in the isotropic phase. Both experiments (rheology and SANS) indicate that the polymer system appears frozen on millimeter length scales and at the time scales of the observation. This result implies that the flow behavior is not the terminal behavior and that cross-links or entanglements are not a necessary condition to provide elasticity in melts.
Flexible synthesis of pyrimidines with chiral monofluorinated and difluoromethyl side chains.
Bannwarth, Pierre; Valleix, Alain; Grée, Danielle; Grée, René
Chiral pyrimidines with a fluorine atom in the benzylic position are easily accessible in high enantiomeric excesses from optically active propargylic intermediates by two complementary routes. Both the use of optically active propargylic fluorides and the fluorination of the chiral pyrimidine in the final stage give excellent results in terms of enantiocontrol. On the other hand, original pyrimidines with a difluoromethyl side chain are also obtained in a few steps from new propargylic ketones bearing a CHF(2) substituent on the triple bond. PMID:19518154
Triazatriangulenium adlayers on Au(111): Superstructure as a function of alkyl side chain length
NASA Astrophysics Data System (ADS)
Lemke, Sonja; Ulrich, Sandra; Claußen, Frauke; Bloedorn, Andreas; Jung, Ulrich; Herges, Rainer; Magnussen, Olaf M.
The structure of organic adlayers, formed by self-assembly of molecular platforms of triazatriangulenium ions on Au(111), was systematically studied by scanning tunneling microscopy as a function of the length of the lateral ligands for alkyl side chains from propyl to dodecyl. A series of hexagonally-ordered adlayers with spacings from 10.7 Å (propyl) to 13.6 Å (dodecyl) was found which are commensurate to the Au(111) substrate lattice, indicating localized bonding of the molecules to the metal.
Synthesis of β-1,4-Linked Galactan Side-Chains of Rhamnogalacturonan I.
Andersen, Mathias C F; Kračun, Stjepan K; Rydahl, Maja G; Willats, William G T; Clausen, Mads H
The synthesis of linear- and (1→6)-branched β-(1→4)-d-galactans, side-chains of the pectic polysaccharide rhamnogalacturonan I is described. The strategy relies on iterative couplings of n-pentenyl disaccharides followed by a late stage glycosylation of a common hexasaccharide core. Reaction with a covalent linker and immobilization on N-hydroxysuccinimide (NHS)-modified glass surfaces allows the generation of carbohydrate microarrays. The glycan arrays enable the study of protein-carbohydrate interactions in a high-throughput fashion, demonstrated herein with binding studies of mAbs and a CBM. PMID:27305141
Synthesis of a new β-amino acid with a 3-deoxy-L-ara furnaoside side chain: the influence of the side chain on the conformation of α/β-peptides.
Sharma, Gangavaram V M; Anjaiah, Gonuguntla; Kanakaraju, Marumudi; Sudhakar, Bommeda; Chatterjee, Deepak; Kunwar, Ajit C
The important role of side chains in the stabilization of helical folds in peptidic foldamers containing C-linked carbo-β-amino acids (β-Caa), an interesting class of β-amino acids, with carbohydrate side chains has been extensively elaborated. As a pragmatic approach to alleviate the interference of substituents in the side chains on the folding propensities of the peptides, they are often modified or removed. The present study reports the synthesis of a new β-Caa with a 3-deoxy-L-ara furanoside side chain, [(R)-β-Caa(da)], from D-glucose, and its use in the synthesis of α/β-peptides in 1 : 1 alternation with D-Ala. The synthesis of peptides using (R)-β-Caa(da), was facile unlike those from (R)-β-Caa(a) having the L-ara furanoside side chain. The detailed NMR, molecular dynamics (MD) and CD studies on the new α/β-peptides showed the presence of robust left-handed 11/9-mixed helices. The study demonstrates that the new (R)-β-Caa(da), behaves differently compared to the other two related monomers, (R)-β-Caa(x) with the D-xylo furanoside side chain and (R)-β-Caa(a). PMID:26489370
Side chain engineering of poly-thiophene and its impact on crystalline silicon based hybrid solar cells
Zellmeier, M.; Rappich, J.; Nickel, N. H.; Klaus, M.; Genzel, Ch.; Janietz, S.; Frisch, J.; Koch, N.
The influence of ether groups in the side chain of spin coated regioregular polythiophene derivatives on the polymer layer formation and the hybrid solar cell properties was investigated using electrical, optical, and X-ray diffraction experiments. The polymer layers are of high crystallinity but the polymer with 3 ether groups in the side chain (P3TOT) did not show any vibrational fine structure in the UV-Vis spectrum. The presence of ether groups in the side chains leads to better adhesion resulting in thinner and more homogeneous polymer layers. This, in turn, enhances the electronic properties of the planar c-Si/poly-thiophene hybrid solar cell. We find that the power conversion efficiency increases with the number of ether groups in the side chains, and a maximum power conversion efficiency of η = 9.6% is achieved even in simple planar structures.
Phase Structures and Transition of Side-Chain Liquid Crystalline Polyacetylene
NASA Astrophysics Data System (ADS)
Chen, Er-Qiang; Ye, Chun; Cheng, S. Z. D.; Lam, Jacky W. Y.; Tang, Ben-Zhong
A side-chain liquid crystalline polyacetylene, poly(5-[(4'-heptoxy-4-biphenylyl) carbonyl]oxy-1-pentyne) (-CH=C[(CH_2)3-OCO-Biph-OC_7H_15]n-), was synthesized. The polymerization catalyzed by WCl_6-Ph_4Sn under optimal condition produced the polymer of high molecular weight (up to 1.2 x 10^5), with predominantly a trans structure of good stereo-regularity. Both the smectic A (SA) and C (SC) phases were found, giving the d spacings of 2.3 and 3.3 nm, respectively. The coexistence of SA and SC is possible at low temperature range due to the specific molecular shape of the sample. Three broad transitions were observed upon heating: the flexible alkyl tails of the side-chain melts at 90 °C approximately, and the transformations from SA and SC to an isotropic melt occur at the peak temperatures of 160 and 170 °C, respectively. The separated SA and SC structures were obtained by the STM scanning at room temperature.
SCWRL and MolIDE: Computer programs for side-chain conformation prediction and homology modeling
Wang, Qiang; Canutescu, Adrian A.; Dunbrack, Roland L.
SCWRL and MolIDE are software applications for prediction of protein structures. SCWRL is designed specifically for the task of prediction of side-chain conformations given a fixed backbone usually obtained from an experimental structure determined by X-ray crystallography or NMR. SCWRL is a command-line program that typically runs in a few seconds. MolIDE provides a graphical interface for basic comparative (homology) modeling using SCWRL and other programs. MolIDE takes an input target sequence, and uses PSI-BLAST to identify and align templates for comparative modeling of the target. The sequence alignment to any template can be manually modified within a graphical window of the target-template alignment and visualization of the alignment on the template structure. MolIDE builds the model of the target structure based on the template backbone, predicted side-chain conformations with SCWRL, and a loop-modeling program for insertion-deletion regions with user-selected sequence segments. SCWRL and MolIDE can be obtained at http://dunbrack.fccc.edu/Software.php. PMID:18989261
Characterization and Diagnostic Value of Amino Acid Side Chain Neutral Losses Following Electron-Transfer Dissociation
NASA Astrophysics Data System (ADS)
Xia, Qiangwei; Lee, M. Violet; Rose, Christopher M.; Marsh, Alyce J.; Hubler, Shane L.; Wenger, Craig D.; Coon, Joshua J.
Using a large set of high mass accuracy and resolution ETD tandem mass spectra, we characterized ETD-induced neutral losses. From these data we deduced the chemical formula for 20 of these losses. Many of them have been previously observed in electron-capture dissociation (ECD) spectra, such as losses of the side chains of arginine, aspartic acid, glutamic acid, glutamine, asparagine, leucine, histidine, and carbamidomethylated cysteine residues. With this information, we examined the diagnostic value of these amino acid-specific losses. Among 1285 peptide-spectrum matches, 92.5% have agreement between neutral loss-derived peptide amino acid composition and the peptide sequences. Moreover, we show that peptides can be uniquely identified by using only the accurate precursor mass and amino acid composition based on neutral losses; the median number of sequence candidates from an accurate mass query is reduced from 21 to 8 by adding side chain loss information. Besides increasing confidence in peptide identification, our findings suggest the potential use of these diagnostic losses in ETD spectra to improve false discovery rate estimation and to enhance the performance of scoring functions in database search algorithms.
Electronic absorption spectroscopy probed side-chain movement in chromic transitions of polydiacetylene vesicles.
Potisatityuenyong, Anupat; Rojanathanes, Rojrit; Tumcharern, Gamolwan; Sukwattanasinitt, Mongkol
Thermochromism, solvatochromism, and alkalinochromism of a poly-10,12-pentacosadiynoic acid (poly(PCDA)) vesicle solution are studied by electronic absorption spectroscopy. The spectroscopic profiles reveal different sequences of side-chain movement during the chromic transitions. The gradual hypsochromic shift and reversibility of the purple solution at low temperature in the thermochromic transition indicates that the transition starts with reversible conformational alteration of methylene side chains leading to metastable purple vesicles. Further heating to 80 degrees C or higher eventually causes the hydrogen bonds at the carboxylic head groups to break and turns the vesicle solution to red. The irreversibility of the red vesicles indicates that it is the most thermodynamically stable form. In the ethanolochromism and alkalinochromism, the processes are however induced at the vesicle-media interface, directly bringing about the hydrogen bond breaking. The purple solutions observed in the ethanolochromism and alkalinochromism cannot reverse back to the blue one. The absorption spectra clearly demonstrate that they are mixtures of the blue and red vesicles. PMID:18366237
An experimental and theoretical study of the amino acid side chain Raman bands in proteins
NASA Astrophysics Data System (ADS)
Sjöberg, Béatrice; Foley, Sarah; Cardey, Bruno; Enescu, Mironel
The Raman spectra of a series of tripeptides with the basic formula GlyAAGly where the central amino acid (AA) was tryptophan, tyrosine, phenylalanine, glycine, methionine, histidine, lysine and leucine were measured in H2O. The theoretical Raman spectra obtained using density functional theory (DFT) calculations at the B3LYP/6-311+G(2df,2pd) level of theory allows a precise attribution of the vibrational bands. The experimental results show that there is a blue shift in the frequencies of several bands of the amino acid side chains in tripeptides compared to free amino acids, especially in the case of AAs containing aromatic rings. On the other hand, a very good agreement was found between the Raman bands of AA residues in tripeptides and those measured on three model proteins: bovine serum albumin, β-lactoglobulin and lysozyme. The present analysis contributes to an unambiguous interpretation of the protein Raman spectra that is useful in monitoring the biological reactions involving AA side chains alteration.
Role of side-chain interactions on the formation of α -helices in model peptides
NASA Astrophysics Data System (ADS)
Mahmoudinobar, Farbod; Dias, Cristiano L.; Zangi, Ronen
The role played by side-chain interactions on the formation of α -helices is studied using extensive all-atom molecular dynamics simulations of polyalanine-like peptides in explicit TIP4P water. The peptide is described by the OPLS-AA force field except for the Lennard-Jones interaction between Cβ-Cβ atoms, which is modified systematically. We identify values of the Lennard-Jones parameter that promote α -helix formation. To rationalize these results, potentials of mean force (PMF) between methane-like molecules that mimic side chains in our polyalanine-like peptides are computed. These PMF exhibit a complex distance dependence where global and local minima are separated by an energy barrier. We show that α -helix propensity correlates with values of these PMF at distances corresponding to Cβ-Cβ of i -i +3 and other nearest neighbors in the α -helix. In particular, the set of Lennard-Jones parameters that promote α -helices is characterized by PMF that exhibit a global minimum at distances corresponding to i -i +3 neighbors in α -helices. Implications of these results are discussed.
Cholesterol side chain analogs but not its ether analogs possess cholesterol-lowering activity.
Lei, Lin; Wang, Xiaobo; Huang, Weihuan; Liu, Yuwei; Zheng, Fangrui; Ma, Ka Ying; Li, Yuk Man; Wang, Lijun; Man, Sun Wa; Zhang, Chengnan; Chen, Zhen-Yu
Cholesterol analogs can be used to treat hypercholesterolemia. The present study was to test the effects of cholesteryl 3β-ethoxy (CE) and cholesteryl 3β-methoxy (CM) on plasma total cholesterol (TC) compared with that of β-sitosterol (SI) in hamsters fed a high cholesterol diet. CM and CE are the methoxy and ethoxy analogs of cholesterol while SI is an analog of cholesterol having an additional ethyl group on the side chain. Results showed that SI at a dose of 0.1% could effectively reduce plasma TC by 18%. The analysis of sterols in the plasma and liver did not detect the presence of SI, proving that it was poorly absorbed in the intestine. In contrast, both CE and CM had no effect on plasma TC. However, CE and CM were found to accumulate in both plasma and liver, indicating that they could be well absorbed in the intestine. It was therefore concluded that analogs having different side chains possessed plasma TC-lowering activity, while analogs or derivatives on the hydroxyl group had no hypocholesterolemic activity. PMID:25536519
Proton spin-lattice relaxation in silkworm cocoons: physisorbed water and serine side-chain motions.
Geppi, Marco; Mollica, Giulia; Borsacchi, Silvia; Cappellozza, Silvia
The molecular dynamic behavior of silkworm cocoons produced by a single Bombyx mori strain was investigated by means of high- and low-resolution solid-state NMR experiments. Cocoons with different moisture content were prepared to study the effects of physisorbed water on their molecular dynamics in the MHz regime, which was probed through the measurement of (1)H T(1) relaxation times at 25 MHz in the 25-95 degrees C temperature range. The water content of the different samples was determined from the analysis of (1)H free-induction decays. In addition to the rotation of methyl groups, mostly from alanine, and to the reorientation of physisorbed water molecules, already identified in previous works as relaxation sinks, the reorientation of serine side-chains was here found to contribute to (1)H T(1) above room temperature. The analysis of the trends of (1)H T(1) versus temperature was carried out in terms of semiempirical models describing the three main motional processes, and indicated that methyl rotation, water reorientation and serine side-chain motions are the most efficient relaxation mechanisms below 0 degrees C, between 0 and 60 degrees C, and above 60 degrees C, respectively. The activation energies were found to decrease passing from serine to water to methyl motions. PMID:20136080
Predictions of the physicochemical properties of amino acid side chain analogs using molecular simulation.
Ahmed, Alauddin; Sandler, Stanley I
A candidate drug compound is released for clinical trails (in vivo activity) only if its physicochemical properties meet desirable bioavailability and partitioning criteria. Amino acid side chain analogs play vital role in the functionalities of protein and peptides and as such are important in drug discovery. We demonstrate here that the predictions of solvation free energies in water, in 1-octanol, and self-solvation free energies computed using force field-based expanded ensemble molecular dynamics simulation provide good accuracy compared to existing empirical and semi-empirical methods. These solvation free energies are then, as shown here, used for the prediction of a wide range of physicochemical properties important in the assessment of bioavailability and partitioning of compounds. In particular, we consider here the vapor pressure, the solubility in both water and 1-octanol, and the air-water, air-octanol, and octanol-water partition coefficients of amino acid side chain analogs computed from the solvation free energies. The calculated solvation free energies using different force fields are compared against each other and with available experimental data. The protocol here can also be used for a newly designed drug and other molecules where force field parameters and charges are obtained from density functional theory. PMID:26864716
Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-D-alanine.
Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Perlikowska, Renata; Adamska, Anna; Olczak, Jacek; Mazur, Marzena; Artali, Roberto; Modranka, Jakub; Janecki, Tomasz; Tömböly, Csaba; Janecka, Anna
Cyclization of linear sequences is a well recognized tool in opioid peptide chemistry for generating analogs with improved bioactivities. Cyclization can be achieved through various bridging bonds between peptide ends or side-chains. In our earlier paper we have reported the synthesis and biological activity of a cyclic peptide, Tyr-c[D-Lys-Phe-Phe-Asp]NH2 (1), which can be viewed as an analog of endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2). Cyclization was achieved through an amide bond between side-chains of D-Lys and Asp residues. Here, to increase rigidity of the cyclic structure, we replaced d-Lys with cis- or trans-4-aminocyclohexyl-D-alanine (D-ACAla). Two sets of analogs incorporating either Tyr or Dmt (2',6'-dimethyltyrosine) residues in position 1 were synthesized. In the binding studies the analog incorporating Dmt and trans-D-ACAla showed high affinity for both, μ- and δ-opioid receptors (MOR and DOR, respectively) and moderate affinity for the κ-opioid receptor (KOR), while analog with Dmt and cis-D-ACAla was exceptionally MOR-selective. Conformational analyses by NMR and molecular docking studies have been performed to investigate the molecular structural features responsible for the noteworthy MOR selectivity. PMID:25456075
A new classification of the amino acid side chains based on doublet acceptor energy levels.
Sneddon, S F; Morgan, R S; Brooks, C L
We describe a new classification of the amino acid side chains based on the potential energy level at which each will accept an extra (doublet) electron. The doublet acceptor energy level, and the doublet acceptor orbital were calculated using semiempirical INDO/2-UHF molecular orbital theory. The results of these calculations show that the side chains fall into four groups. We have termed these groups repulsive, insulating, semiconducting, and attractive in accordance with where each lies on the relative energy scale. We use this classification to examine the role of residues between the donor and acceptor in modulating the rate and mechanism of electron transfer in proteins. With the calculated acceptor levels, we construct a potential barrier for those residues between the donor and acceptor. It is the area beneath this barrier that determines the decay of electronic coupling between donor and acceptor, and thus the transfer rate. We have used this schematic approach to characterize the four electron transfer pathways in myoglobin recently studied by Mayo et al. (Mayo, S.L., W.R. Ellis, R.J. Crutchley, and H.B. Gray. 1986. Science [Wash. DC]. 233:948-952). PMID:3342271
Histidine side-chain dynamics and protonation monitored by 13C CPMG NMR relaxation dispersion.
Hass, Mathias A S; Yilmaz, Ali; Christensen, Hans E M; Led, Jens J
The use of 13C NMR relaxation dispersion experiments to monitor micro-millisecond fluctuations in the protonation states of histidine residues in proteins is investigated. To illustrate the approach, measurements on three specifically 13C labeled histidine residues in plastocyanin (PCu) from Anabaena variabilis (A.v.) are presented. Significant Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion is observed for 13C(epsilon1) nuclei in the histidine imidazole rings of A.v. PCu. The chemical shift changes obtained from the CPMG dispersion data are in good agreement with those obtained from the chemical shift titration experiments, and the CPMG derived exchange rates agree with those obtained previously from 15N backbone relaxation measurements. Compared to measurements of backbone nuclei, 13C(epsilon1) dispersion provides a more direct method to monitor interchanging protonation states or other kinds of conformational changes of histidine side chains or their environment. Advantages and shortcomings of using the 13C(epsilon1) dispersion experiments in combination with chemical shift titration experiments to obtain information on exchange dynamics of the histidine side chains are discussed. PMID:19533375
Proton exchange membranes based on the short-side-chain perfluorinated ionomer
NASA Astrophysics Data System (ADS)
Ghielmi, A.; Vaccarono, P.; Troglia, C.; Arcella, V.
Due to the renovated availability of the base monomer for the synthesis of the short-side-chain (SSC) perfluorinated ionomer, fuel cell membrane development is being pursued using this well known ionomer structure, which was originally developed by Dow in the 1980s. The new membranes under development have the trade name Hyflon Ion. After briefly reviewing the literature on the Dow ionomer, new characterization data are reported on extruded Hyflon Ion membranes. The data are compared to those available in the literature on the Dow SSC ionomer and membranes. Comparison is made also with data obtained in this work or available in the literature on the long-side-chain (LSC) perfluorinated ionomer (Nafion). Thermal, visco-elastic, water absorption and mechanical properties of Hyflon Ion are studied. While the general behavior is similar to that shown in the past by the Dow membranes, slight differences are evident in the hydration behavior at equivalent weight (EW) < 900, probably due to different EW distributions. Measurements on dry membranes confirm that Hyflon Ion has a higher glass transition temperature compared to Nafion, which makes it a more promising material for high temperature proton exchange membrane (PEM) fuel cell operation ( T > 100 °C). Beginning of life fuel cell performance has also been confirmed to be higher than that given by a Nafion membrane of equal thickness.
Efficient rotamer elimination applied to protein side-chains and related spin glasses.
Goldstein, R F
Folded proteins and spin glasses share various properties, such as seemingly random interactions between residues (spins), and one might presume that some generic behaviors of spin glasses would also be exhibited in a general way by proteins. But a comparison here shows that the side-chain conformation systems of apo-myoglobin and lysozyme are qualitatively different from specific closely related spin glass systems. This difference is manifest in the number of rotamers that can be identified as definitely not contributing to the global energy minimum. This identification is effected by using a significantly enhanced version of the Dead End Elimination theorem (Desmet, J., M. De Maeyer, B. Hazes, and I. Lasters. 1992. The dead-end elimination theorem and its use in protein side-chain positioning. Nature. 356:539-542), which is much more effective and efficient in eliminating rotamers. In several cases (for proteins, although not for spin glasses) this improved Dead End Elimination theorem succeeded in identifying the absolute global minimum of rotamer conformations, with no statistical uncertainty. The difference between protein and spin glass is due to correlations between the interactions of one residue pair with another pair, and probably will play an important role in the thermodynamic behavior of the protein system. PMID:8061189
Antibody conjugates with unnatural amino acids.
Hallam, Trevor J; Wold, Erik; Wahl, Alan; Smider, Vaughn V
Antibody conjugates are important in many areas of medicine and biological research, and antibody-drug conjugates (ADCs) are becoming an important next generation class of therapeutics for cancer treatment. Early conjugation technologies relied upon random conjugation to multiple amino acid side chains, resulting in heterogeneous mixtures of labeled antibody. Recent studies, however, strongly support the notion that site-specific conjugation produces a homogeneous population of antibody conjugates with improved pharmacologic properties over randomly coupled molecules. Genetically incorporated unnatural amino acids (uAAs) allow unique orthogonal coupling strategies compared to those used for the 20 naturally occurring amino acids. Thus, uAAs provide a novel paradigm for creation of next generation ADCs. Additionally, uAA-based site-specific conjugation could also empower creation of additional multifunctional conjugates important as biopharmaceuticals, diagnostics, or reagents. PMID:25898256
Dual mesomorphic assemblage of chitin normal acylates and rapid enthalpy relaxation of their side chains.
Teramoto, Yoshikuni; Miyata, Tomoya; Nishio, Yoshiyuki
Chitin derivatives having normalacyl groups (C(n)H(2n-1)O-; n = 4-20) were synthesized with pyridine, p-toluenesulfonyl chloride, and normal alkanoic acid in an N,N-dimethylacetamide-lithium chloride homogeneous system. The products (C(n)-ACs; degree of acyl substitution, DS = 1.7-1.9) showed an n-dependent thermal transition behavior: no evident transition (n = 4-10), a glass transition (n = 12 and 14), and a pseudo-first-order phase transition (n = 16-20), the latter two occurring usually below room temperature when examined by differential scanning calorimetry. Wide-angle X-ray diffractometry (WAXD) at 20 degrees C displayed a sharp diffraction peak (2theta = 2 degrees -7 degrees ) and a diffuse halo (2theta approximately 20 degrees ) for the respective C(n)-ACs. The former d-spacing (1.5-3.6 nm) increased with an increase in n to yield two stages of mutually different increasing rates, which reflects a systematic n-dependence of the period of a layered structure of the main chains. The molecular assembly of C(n)-ACs exhibited "dual mesomorphy"; nematic ordering for the semirigid carbohydrate trunk and smectic one for the flexible side chains. On the other hand, WAXD profiles of C(n)-ACs (n = 14-18) indicated almost no temperature dependence from -150 to +220 degrees C. Therefore, it was reasonably assumed that the pseudo-first-order transition observed in thermograms of C(n)-ACs (n = 16-20) was due to the enthalpy relaxation of the side-chain assemblage. An insight was provided into the kinetics of the characteristic aging behavior as a liquid-crystalline glass, in comparison with the corresponding data for other noncrystalline macromolecules. PMID:16398515
Physics-based side-chain-rotamer and side-chain and backbone virtual-bond-stretching potentials for coarse-grained UNRES force field. 2. Comparison with statistical potentials and implementation
Kozłowska, Urszula; Maisuradze, Gia G.; Liwo, Adam; Scheraga, Harold A.
Using the harmonic-approximation approach of the accompanying paper and AM1 energy surfaces of terminally-blocked amino-acid residues, we determined physics-based side-chain-rotamer potentials and the side-chain virtual-bond-deformation potentials of 19 natural amino-acid residues with side chains. The potentials were approximated by analytical formulas and implemented in the UNRES mesoscopic dynamics program. For comparison, the corresponding statistical potentials were determined from 19,682 high-resolution protein structures. The low-free-energy region of both the AM1-derived and the statistical potentials is determined by the valence geometry and the L-chirality, and its size increases with side-chain flexibility and decreases with increasing virtual-bond-angle θ. The differences between the free energies of rotamers are greater for the AM1-derived potentials compared to the statistical potentials and, for alanine and other residues with small side chains, a region corresponding to the Cax7 conformation has remarkably low free energy for the AM1-derived potentials, as opposed to the statistical potentials. These differences probably result from the interactions between neighboring residues and indicate the need for introduction of cooperative terms accounting for the coupling between side-chain-rotamer and backbone interactions. Both AM1-derived and statistical virtual-bond-deformation potentials are multimodal for flexible side chains and are topologically similar; however, the regions of minima of the statistical potentials are much narrower, which probably results from imposing restraints in structure determination. The force field with the new potentials was preliminarily optimized using the FBP WW domain (1E0L) and the engrailed homeodomain (1ENH) as training proteins and assessed to be reasonably transferable. PMID:20017135
The effect of junction modes between backbones and side chains of polyimides on the stability of liquid crystal vertical alignment.
Che, Xinyuan; Gong, Shiming; Zhang, Heng; Liu, Bin; Wang, Yinghan
Polyimides (PI-N9 and PI-N12) were synthesized from two kinds of functional diamines, whose junction modes between backbones and side chains were different. Side chains of PI-N9 were linked to the backbones with an ether bond spacer; and side chains of PI-N12 were directly linked to the backbones without any spacer. The PI alignment layer surfaces were investigated by atomic force microscopy, surface free energy measurements, X-ray photo-electron spectroscopy and polarized attenuated total reflection Fourier transformed infrared spectroscopy. It was found that PI-N9 lost the vertical alignment capability after high-strength rubbing, while PI-N12 could still induce liquid crystals (LCs) to align vertically under the same condition. The mechanism of the macroscopic molecular orientation of the PI surface is proposed. During the high-strength rubbing process, the side chain could rotate around the flexible ether bond which existed between the side chain and the main chain of PI-N9 and then fell over. Therefore, PI-N9 could not induce the vertical alignment of LCs anymore. But PI-N12 could keep LCs aligning vertically all the time, which proved that the stability of LC alignment induced by PI-N12 was better. PMID:26766667
Lattice and off-lattice side chain models of protein folding: Linear time structure prediction better than 86% of optimal
Hart, W.E.; Istrail, S.
This paper considers the protein structure prediction problem for lattice and off-lattice protein folding models that explicitly represent side chains. Lattice models of proteins have proven extremely useful tools for reasoning about protein folding in unrestricted continuous space through analogy. This paper provides the first illustration of how rigorous algorithmic analyses of lattice models can lead to rigorous algorithmic analyses of off-lattice models. The authors consider two side chain models: a lattice model that generalizes the HP model (Dill 85) to explicitly represent side chains on the cubic lattice, and a new off-lattice model, the HP Tangent Spheres Side Chain model (HP-TSSC), that generalizes this model further by representing the backbone and side chains of proteins with tangent spheres. They describe algorithms for both of these models with mathematically guaranteed error bounds. In particular, the authors describe a linear time performance guaranteed approximation algorithm for the HP side chain model that constructs conformations whose energy is better than 865 of optimal in a face centered cubic lattice, and they demonstrate how this provides a 70% performance guarantee for the HP-TSSC model. This is the first algorithm in the literature for off-lattice protein structure prediction that has a rigorous performance guarantee. The analysis of the HP-TSSC model builds off of the work of Dancik and Hannenhalli who have developed a 16/30 approximation algorithm for the HP model on the hexagonal close packed lattice. Further, the analysis provides a mathematical methodology for transferring performance guarantees on lattices to off-lattice models. These results partially answer the open question of Karplus et al. concerning the complexity of protein folding models that include side chains.
Shape-Selectivity with Liquid Crystal and Side-Chain Liquid Crystalline Polymer SAW Sensor Interfaces
A liquid crystal (LC) and a side-chain liquid crystalline polymer (SCLCP) were tested as surface acoustic wave (SAW) vapor sensor coatings for discriminating between pairs of isomeric organic vapors. Both exhibit room temperature smectic mesophases. Temperature, electric-field, and pretreatment with self-assembled monolayers comprising either a methyl-terminated or carboxylic acid-terminated alkane thiol anchored to a gold layer in the delay path of the sensor were explored as means of affecting the alignment and selectivity of the LC and SCLCP films. Results for the LC were mixed, while those for the SCLCP showed a consistent preference for the more rod-like isomer of each isomer pair examined.
Inducing Planar Orientation in Side-Chain Liquid-Crystalline Polymer Systems via Interfacial Control.
Nagano, Shusaku
For efficient photoresponses of liquid-crystal (LC) azobenzene (Az) polymer systems, planar LC orientation of the Az mesogenic group is required because the light irradiation process usually occurs with normal incidence to the film surface. However, LC molecules with a rodlike shape tend to orient perpendicularly to the film surface according to the excluded volume effect theory. This review introduces new approaches for inducing planar orientation in side-chain LC Az polymer films via interface and surface molecular designs. The planar orientation offers efficient in-plane photoalignment and photoswitching to hierarchical LC architectures from molecular LC mesogens and LC phases to mesoscopic microphase-separated structures. These approaches are expected to provide new concepts and possibilities in new LC polymer devices. PMID:26775770
Electrostatic Control of Peptide Side-Chain Reactivity using Amphiphilic Homopolymer-based Supramolecular Assemblies
Wang, Feng; Gomez-Escudero, Andrea; Ramireddy, Rajasekhar R.; Murage, Gladys
Supramolecular assemblies formed by amphiphilic homopolymers with negatively charged groups in the hydrophilic segment have been designed to enable high labeling selectivity towards reactive side chain functional groups in peptides. The negatively-charged interiors of the supramolecular assemblies are found to block the reactivity of protonated amines that would otherwise be reactive in aqueous solution, while maintaining the reactivity of non-protonated amines. Simple changes to the pH of the assemblies' interiors allow control over the reactivity of different functional groups in a manner that is dependent on the pKa of a given peptide functional group. The labeling studies carried out in positively charged supramolecular assemblies and free buffer solution show that, even when the amine is protonated, labeling selectivity exists only when complementary electrostatic interactions are present, thereby demonstrating the electrostatically controlled nature of these reactions. PMID:23971726
Calcium ions induce collapse of charged O-side chains of lipopolysaccharides from Pseudomonas aeruginosa
Schneck, Emanuel; Papp-Szabo, Erzsebet; Quinn, Bonnie E.; Konovalov, Oleg V.; Beveridge, Terry J.; Pink, David A.; Tanaka, Motomu
Lipopolysaccharide (LPS) monolayers deposited on planar, hydrophobic substrates were used as a defined model of outer membranes of Pseudomonas aeruginosa strain dps 89. To investigate the influence of ions on the (out-of-plane) monolayer structure, we measured specular X-ray reflectivity at high energy (22 keV) to ensure transmission through water. Electron density profiles were reconstructed from the reflectivity curves, and they indicate that the presence of Ca2+ ions induces a significant change in the conformation of the charged polysaccharide head groups (O-side chains). Monte Carlo simulations based on a minimal computer model of LPS molecules allow for the modelling of 100 or more molecules over 10−3 s and theoretically explained the tendency found by experiments. PMID:19605401
Synthesis of brassinosteroids with a keto group in the side chain.
Baradzenka, Aliona G; Barysau, Barys M; Hurski, Alaksiej L; Zhabinskii, Vladimir N; Khripach, Vladimir A
The aim of this work was to prepare 24-epicryptolide and 22-dehydro-24-epibrassinolide as possible metabolites of 24-epibrassinolide. The main synthetic problem to be solved was the differentiation of functional groups in brassinosteroids. Distinguishing 2α,3α-diol function from another diol group in 24-epibrassinolide was achieved via selective hydrolysis of 2α,3α-cyclic carbonate or via regioselective reaction of boric acid with the functional groups in the side chain. The hydroxyl at C-23 was more reactive than the 22-OH in the oxidation with bromine in the presence of bis(tributyltin) oxide and in the benzylation reaction that resulted in the predominant formation of the corresponding α-hydroxy ketone derivatives with the ratio ranging from 4:1 to 1.5:1. PMID:26079654
Poly-dimethylsiloxane derivates side chains effect on syntan functionalized Polyamide fabric
NASA Astrophysics Data System (ADS)
Migani, V.; Weiss, H.; Massafra, M. R.; Merlo, A.; Colleoni, C.; Rosace, G.
Poly-dimethylsiloxane (PDMS) polymers finishing of Polyamide-6,6 (PA66) fabrics involves ionic interactions between reactive groups on the PDMS polymers and the ones of the textile fabric. Such interactions could be strengthened by a pretreatment with a fixing agent to promote either ion-ion and H-bonding and ion-dipole forces. These forces could contribute towards the building of substantial PDMS-PA66 systems and the achieving of better adhesion properties to fabrics. Four different silicone polymers based on PDMS were applied on a synthetic tanning agent (syntan) finished Polyamide-6,6 fabric under acid conditions. Soxhlet extraction method and ATR FT-IR technique were used to investigate the application conditions. The finishing parameters such as pH and temperature together with fastness, mechanical and performance properties of the treated samples were studied and related to PDMS side chains effect on syntan functionalized Polyamide fabric.
Side chain and backbone contributions of Phe508 to CFTR folding
Thibodeau, Patrick H.; Brautigam, Chad A.; Machius, Mischa; Thomas, Philip J.
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein, cause cystic fibrosis (CF). The most common CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the role Phe508 plays in the folding of CFTR, missense mutations at this position were generated. Only one missense mutation had a pronounced effect on the stability and folding of the isolated domain in vitro. In contrast, many substitutions, including those of charged and bulky residues, disrupted folding of full-length CFTR in cells. Structures of two mutant nucleotide-binding domains (NBDs) reveal only local alterations of the surface near position 508. These results suggest that the peptide backbone plays a role in the proper folding of the domain, whereas the side chain plays a role in defining a surface of NBD1 that potentially interacts with other domains during the maturation of intact CFTR.
Template-nucleated alanine-lysine helices are stabilized by position-dependent interactions between the lysine side chain and the helix barrel.
Groebke, K; Renold, P; Tsang, K Y; Allen, T J; McClure, K F; Kemp, D S
The helicity in water has been determined for several series of alanine-rich peptides that contain single lysine residues and that are N-terminally linked to a helix-inducing and reporting template termed Ac-Hel1. The helix-propagating constant for alanine (sAla value) that best fits the properties of these peptides lies in the range of 1.01-1.02, close to the value reported by Scheraga and coworkers [Wojcik, J., Altmann, K.-H. & Scheraga, H.A. (1990) Biopolymers 30, 121-134], but significantly lower than the value assigned by Baldwin and coworkers [Chakrabartty, A., Kortemme, T. & Baldwin, R.L. (1994) Protein Sci. 3,843-852]. From a study of conjugates Ac-Hel1-Ala(n)-Lys-Ala(m)-NH2 and analogs in which the methylene portion of the lysine side chain is truncated, we find that the unusual helical stability of Ala(n)Lys peptides is controlled primarily by interactions of the lysine side chain with the helix barrel, and only passively by the alanine matrix. Using 1H NMR spectroscopy, we observe nuclear Overhauser effect crosspeaks consistent with proton-proton contacts expected for these interactions. PMID:8633010
π-Conjugated Copolymers of Thiophene: Effect of Chain Architecture on the Physical and Optoelectronic Properties for Photovoltaic Applications
NASA Astrophysics Data System (ADS)
Amonoo, Jojo; Glynos, Emmanouil; Chen, Chelsea; Li, Anton; Locke, Jonas; McNeil, Anne; Green, Peter
We found that polymer chain architecture strongly influences phase separation capabilities of the donor-acceptor blend in bulk heterojunction organic photovoltaic devices. Ni-catalyzed controlled polymerization was utilized to access new conjugated copolymers of 3-hexylthiophene and 3-(hexyloxy)methylthiophene, two donor polymers. Monomer sequence was controlled along the copolymer chain by the rate of addition of the comonomers, to achieve diblock, random and gradient copolymer chain architectures. This allowed us to study the effect of copolymer sequence of polythiophene based copolymer/[6,6]-phenyl-C61-butyric acid methyl ester (PCBM) blend on the structure, nanoscale morphology and local charge transport properties using conductive and photoconductive atomic force microscopy. The gradient configuration showed the largest phase separation behavior with PCBM.
Multiplicative luminescence enhancement induced by chain relaxation in ultrathin films of a conjugated polymer (MEH-PPV)
NASA Astrophysics Data System (ADS)
Yang, Chih-Wei; Jou, Juo-Huei; Chang-Mou Yang, Arnold
A surprising multiplication of light-emitting efficiency was observed in dewetting process of the conjugated luminescent polymer of poly (2-methoxy- 5-(2'-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV). The luminescent efficiency increased with the dewetting process and became about six-fold when the polymer film ruptured into tiny droplets. This enhancement appeared to be related to the carrier transport mechanisms and the motions of polymer chains. The effects of inter-molecular energy transport and molecular deformation of polymer chains were studied by examining the emission behavior in liquid and solid solutions. It was found that the molecular movements during stretching in the glassy state were quite different from that in the dewetting process. The latter was dominated by disengagement of inter-molecular entanglements while the former was strongly influenced by trapping mechanisms of chain entanglements due to rapid local molecular strains. This work is supported by National Science Council of Taiwan.
Ozonolysis of surface adsorbed methoxyphenols: kinetics of aromatic ring cleavage vs. alkene side-chain oxidation
NASA Astrophysics Data System (ADS)
O'Neill, E. M.; Kawam, A. Z.; Van Ry, D. A.; Hinrichs, R. Z.
Lignin pyrolysis products, which include a variety of substituted methoxyphenols, constitute a major component of organics released by biomass combustion and may play a central role in the formation of atmospheric brown carbon. Understanding the atmospheric fate of these compounds upon exposure to trace gases is therefore critical to predicting the chemical and physical properties of biomass burning aerosol. We used diffuse reflectance infrared spectroscopy to monitor the heterogeneous ozonolysis of 4-propylguaiacol, eugenol, and isoeugenol adsorbed on NaCl and α-Al2O3 substrates. Adsorption of gaseous methoxyphenols onto these substrates produced near monolayer surface concentrations of 3 × 1018 molecules m-2. The subsequent dark heterogeneous ozonolysis of adsorbed 4-propylguaiacol cleaved the aromatic ring between the methoxy and phenol groups with the product conclusively identified by GC-MS and 1H-NMR. Kinetic analysis of eugenol and isoeugenol dark ozonolysis also suggested the formation of ring-cleaved products, although ozonolysis of the unsaturated substituent groups forming carboxylic acids and aldehydes was an order of magnitude faster. Average uptake coefficients for NaCl-adsorbed methoxyphenols were γ = 2.3 (±0.8) × 10-7 and 2 (±1) × 10-6 for ozonolysis of the aromatic ring and the unsaturated side chain, respectively, and reactions on α-Al2O3 were approximately two times slower. UV-visible radiation (λ>300 nm) enhanced eugenol ozonolysis of the aromatic ring by a factor of 4(±1) but had no effect on ozonolysis of the alkene side-chain.
Glutamine and Asparagine Side Chain Hyperconjugation-Induced Structurally Sensitive Vibrations.
Punihaole, David; Hong, Zhenmin; Jakubek, Ryan S; Dahlburg, Elizabeth M; Geib, Steven; Asher, Sanford A
We identified vibrational spectral marker bands that sensitively report on the side chain structures of glutamine (Gln) and asparagine (Asn). Density functional theory (DFT) calculations indicate that the Amide III(P) (AmIII(P)) vibrations of Gln and Asn depend cosinusoidally on their side chain OCCC dihedral angles (the χ3 and χ2 angles of Gln and Asn, respectively). We use UV resonance Raman (UVRR) and visible Raman spectroscopy to experimentally correlate the AmIII(P) Raman band frequency to the primary amide OCCC dihedral angle. The AmIII(P) structural sensitivity derives from the Gln (Asn) Cβ-Cγ (Cα-Cβ) stretching component of the vibration. The Cβ-Cγ (Cα-Cβ) bond length inversely correlates with the AmIII(P) band frequency. As the Cβ-Cγ (Cα-Cβ) bond length decreases, its stretching force constant increases, which results in an upshift in the AmIII(P) frequency. The Cβ-Cγ (Cα-Cβ) bond length dependence on the χ3 (χ2) dihedral angle results from hyperconjugation between the Cδ═Oϵ (Cγ═Oδ) π* and Cβ-Cγ (Cα-Cβ) σ orbitals. Using a Protein Data Bank library, we show that the χ3 and χ2 dihedral angles of Gln and Asn depend on the peptide backbone Ramachandran angles. We demonstrate that the inhomogeneously broadened AmIII(P) band line shapes can be used to calculate the χ3 and χ2 angle distributions of peptides. The spectral correlations determined in this study enable important new insights into protein structure in solution, and in Gln- and Asn-rich amyloid-like fibrils and prions. PMID:26392216
Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants
Larson, Alyssa M.; Chen, Jianzhu; Klibanov, Alexander M.
By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker group on the negatively charged poly-L-glutamate resulted in some of the most potent inhibitors for 2′s conjugates against drug-resistant influenza strains. Although full recovery of the inhibitory action against drug-resistant strains was not achieved, this study may be a step toward salvaging anti-influenza drugs that are no longer effective. PMID:23832466
Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants.
Larson, Alyssa M; Chen, Jianzhu; Klibanov, Alexander M
By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains, we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker group on the negatively charged poly-l-glutamate resulted in one of the most potent inhibitors for 2's conjugates against drug-resistant influenza strains. Although full recovery of the inhibitory action against drug-resistant strains was not achieved, this study may be a step toward salvaging anti-influenza drugs that are no longer effective. PMID:23832466
Multi-functionalized side-chain supramolecular polymers: A methodology towards tunable functional materials
NASA Astrophysics Data System (ADS)
Nair, Kamlesh Prabhakaran
Even as we see a significant growth in the field of supramolecular polymers in the last ten years, multi-functionalized systems have been scarcely studied. Noncovalent multi-functionalization provides unique advantages such as rapid materials optimization via reversible functionalization as well as for the tuning of materials properties by exploiting the differences in the nature of these reversible interactions. This thesis involves the design principles, synthesis & methodology of supramolecular side-chain multi-functionalized polymers. The combination of a functionally tolerant & controlled polymerization technique such as ROMP with multiple noncovalent interactions such as hydrogen bonding, metal coordination and ionic interactions has been successfully used to synthesize these polymers. Furthermore, the orthogonality between the above interactions in block/random copolymers has been studied in detail. It has been found that the studied interactions were orthogonal to each other. To validate the viability of this methodology using multiple orthogonal interactions towards materials design noncovalent crosslinking of polymers has been used as a potential application. Three classes of networks have been studied: complementary multiple hydrogen bonded networks, metal crosslinked networks, & multi-functionalized hydrogen bonded and metal coordinated networks. The first room temperature decrosslinking by exclusive complementary hydrogen bonded interactions has been successfully achieved. Furthermore network properties have been successfully tuned by varying the network micro-structure which in turn was tuned by the hydrogen bonding motifs used for inter-chain crosslinking. By combining two different noncovalent interactions used for inter-chain crosslinking, it was possible to make multi-functionalized materials whose properties could be controlled by varying the crosslinking strategy. Hence by employing multi-functionalization methodology, important materials
Macrocyclization of Peptide Side Chains by the Ugi Reaction: Achieving Peptide Folding and Exocyclic N-Functionalization in One Shot.
Vasco, Aldrin V; Pérez, Carlos S; Morales, Fidel E; Garay, Hilda E; Vasilev, Dimitar; Gavín, José A; Wessjohann, Ludger A; Rivera, Daniel G
The cyclization of peptide side chains has been traditionally used to either induce or stabilize secondary structures (β-strands, helices, reverse turns) in short peptide sequences. So far, classic peptide coupling, nucleophilic substitution, olefin metathesis, and click reactions have been the methods of choice to fold synthetic peptides by means of macrocyclization. This article describes the utilization of the Ugi reaction for the side chain-to-side chain and side chain-to-termini macrocyclization of peptides, thus enabling not only access to stable folded structures but also the incorporation of exocyclic functionalities as N-substituents. Analysis of the NMR-derived structures revealed the formation of helical turns, β-bulges, and α-turns in cyclic peptides cross-linked at i, i + 3 and i, i + 4 positions, proving the folding effect of the multicomponent Ugi macrocyclization. Molecular dynamics simulation provided further insights on the stability and molecular motion of the side chain cross-linked peptides. PMID:26030840
Synthesis and Photophysical and Electroluminescent Properties of Poly(1,4-phenylene–ethynylene)-alt-poly(1,4-phenylene–vinylene)s with Various Dissymmetric Substitution of Alkoxy Side Chains
The synthesis and characterization of a set of conjugated polymers, poly(1,4-phenylene–ethynylene)-alt-poly(1,4-phenylene–vinylene)s (PPE–PPVs), with a dissymmetrical configuration (partial or total) of alkoxy side chains is reported. Five new polymers bearing octyloxy and/or octadecyloxy side chains at the phenylene–ethynylene and phenylene–vinylene segments, respectively, were obtained. Two symmetrical substituted polymers were used for comparison. Polymers with weight-average molecular weight, Mw, up to 430 000 g/mol and degree of polymerization between 17 and 322 were obtained by a Horner–Wadsworth–Emmons olefination polycondensation reaction of the respective luminophoric dialdehydes and bisphosphonates. As expected, identical conjugated backbones in all polymers results in very similar photophysical response in dilute solution, with high fluorescence quantum yields between 50% and 80%. In contrast, the thin film properties are dependent on the combinatorial effects of side chain configuration, molecular weight, and film thickness parameters, which are the basis of the resulting comparison and discussion. PMID:26877550
Structure-activity relationships of C1 and C6 side chains of zaragozic acid A derivatives.
Ponpipom, M M; Girotra, N N; Bugianesi, R L; Roberts, C D; Berger, G D; Burk, R M; Marquis, R W; Parsons, W H; Bartizal, K F; Bergstom, J D
Systematic modification of the C6 acyl side chain of zaragozic acid A, a potent squalene synthase inhibitor, was undertaken to improve its biological activity. Simplification of the C6 side chain to the octanoyl ester has deleterious effects; increasing the linear chain length improves the in vitro activity up to the tetradecanoyl ester. An omega-phenoxy group is a better activity enhancer than an omega-phenyl group. A number of C6 carbamates, ethers, and carbonates were prepared and found to have similar activity profiles as the C6 esters. In the preparation of C6 ethers, C4 and C4,6 bisethers were also isolated; their relative activity is: C6 > C4 > C4,6. These C6 long-chain derivatives are subnanomolar squalene synthase inhibitors; they are, however, only weakly active in inhibiting hepatic cholesterol synthesis in mice. The C6 short-chain derivatives are much less active in vitro, but they all have improved oral activity in mice. Modification of the C1 alkyl side chain of the n-butanoyl analogue (ED50 4.5 mg/kg) did not improve the po activity further. A number of these C6 long-chain derivatives are also potent antifungal agents in vitro. PMID:7966163
Role of Side-Chain Molecular Features in Tuning Lower Critical Solution Temperatures (LCSTs) of Oligoethylene Glycol Modified Polypeptides.
Gharakhanian, Eric G; Deming, Timothy J
A series of thermoresponsive polypeptides has been synthesized using a methodology that allowed facile adjustment of side-chain functional groups. The lower critical solution temperature (LCST) properties of these polymers in water were then evaluated relative to systematic molecular modifications in their side-chains. It was found that in addition to the number of ethylene glycol repeats in the side-chains, terminal and linker groups also have substantial and predictable effects on cloud point temperatures (Tcp). In particular, we found that the structure of these polypeptides allowed for inclusion of polar hydroxyl groups, which significantly increased their hydrophilicity and decreased the need to use long oligoethylene glycol repeats to obtain LCSTs. The thioether linkages in these polypeptides were found to provide an additional structural feature for reversible switching of both polypeptide conformation and thermoresponsive properties. PMID:27102972
Frequent Side Chain Methyl Carbon-Oxygen Hydrogen Bonding in Proteins Revealed by Computational and Stereochemical Analysis of Neutron Structures
Brooks, Charles L.; Trievel, Raymond C.
The propensity of backbone Cα atoms to engage in carbon-oxygen (CH···O) hydrogen bonding is well-appreciated in protein structure, but side chain CH···O hydrogen bonding remains largely uncharacterized. The extent to which side chain methyl groups in proteins participate in CH···O hydrogen bonding is examined through a survey of neutron crystal structures, quantum chemistry calculations, and molecular dynamics simulations. Using these approaches, methyl groups were observed to form stabilizing CH···O hydrogen bonds within protein structure that are maintained through protein dynamics and participate in correlated motion. Collectively, these findings illustrate that side chain methyl CH···O hydrogen bonding contributes to the energetics of protein structure and folding. PMID:25401519
Effect of alkyl side-chain length on the photophysical, morphology and photoresponse properties of poly(3-alkylthiophene)
NASA Astrophysics Data System (ADS)
Xu, Wei-Long; Yang, Xiao-Yu; Zheng, Fei; Jin, Han-Dong; Hao, Xiao-Tao
The effect of alkyl side-chain length on the photophysical, morphology and photoresponse properties of poly (3-alkylthiophene) (P3AT) has been investigated. Butyl, hexyl, octyl, decyl, and dodecyl side chains have been studied. In solution state, the average lifetime of poly (3-octylthiophene) (P3OT) is the shortest among P3AT solution owing to the strong intrachain interaction. The fluorescence lifetime of P3AT solution increases with the side-chain length increasing. A similar trend occurs in the P3AT films. This phenomenon illustrates conformation 'memory' property evolving from solution state to solid film. The four lifetimes represent different photophysical processes and have been systematically analyzed. The photodetector based on P3DDT is a suitable candidate for practical application owing to the fast, reversible photoresponse and photostability. The high performance of P3DDT-based photodetector is correlated to the optimized morphology and strong interchain interaction which promotes the exciton delocalization.
New Carbon Allotropes with Helical Chains of Complementary Chirality Connected by Ethene-type π-Conjugation
Wang, Jian-Tao; Chen, Changfeng; Kawazoe, Yoshiyuki
We here identify by ab initio calculations two distinct three-dimensional three-connected (3D3C) chiral framework structures of carbon in and I41/amd symmetry, respectively, which comprise 3-fold and 4-fold helical chains with complementary chirality. The helical carbon chains are connected by an ethene-type planar π-conjugation, and the resulting structures contain a network of sp2 carbon bonds with one-third being double bonds between the chains and two-thirds single bonds along the chains. Phonon and electronic band structure calculations show that these chiral carbene structures are dynamically stable and exhibit a large band gap (2.4 ~ 2.9 eV). This semiconducting nature reflects a key distinction from previously proposed metallic isomers of helical or zigzag carbon chains with twisted π states that are dynamically unstable. The present results solve the long-sought 3D3C all-sp2 carbon structures and may help design other covalent bonding networks. PMID:24165546
The Role of fadD19 and echA19 in Sterol Side Chain Degradation by Mycobacterium smegmatis.
Wrońska, Natalia; Brzostek, Anna; Szewczyk, Rafał; Soboń, Adrian; Dziadek, Jarosław; Lisowska, Katarzyna
Mycobacteria are able to degrade natural sterols and use them as a source of carbon and energy. Several genes which play an important role in cholesterol ring degradation have been described in Mycobacterium smegmatis. However, there are limited data describing the molecular mechanism of the aliphatic side chain degradation by Mycobacterium spp. In this paper, we analyzed the role of the echA19 and fadD19 genes in the degradation process of the side chain of cholesterol and β-sitosterol. We demonstrated that the M. smegmatis fadD19 and echA19 genes are not essential for viability. FadD19 is required in the initial step of the biodegradation of C-24 branched sterol side chains in Mycobacterium smegmatis mc²155, but not those carrying a straight chain like cholesterol. Additionally, we have shown that echA19 is not essential in the degradation of either substrate. This is the first report, to our knowledge, on the molecular characterization of the genes playing an essential role in C-24 branched side chain sterol degradation in M. smegmatis mc²155. PMID:27164074
XANES measurements of the rate of radiation damage to selenomethionine side chains
Holton, James M.
The radiation-induced disordering of selenomethionine (SeMet) side chains represents a significant impediment to protein structure solution. Not only does the increased B-factor of these sites result in a serious drop in phasing power, but some sites decay much faster than others in the same unit cell. These radiolabile SeMet side chains decay faster than high-order diffraction spots with dose, making it difficult to detect this kind of damage by inspection of the diffraction pattern. The selenium X-ray absorbance near-edge spectrum (XANES) from samples containing SeMet was found to change significantly after application of X-ray doses of 10–100 MGy. Most notably, the sharp 'white line' feature near the canonical Se edge disappears. The change was attributed to breakage of the Cγ—Se bond in SeMet. This spectral change was used as a probe to measure the decay rate of SeMet with X-ray dose in cryo-cooled samples. Two protein crystal types and 15 solutions containing free SeMet amino acid were examined. The damage rate was influenced by the chemical and physical condition of the sample, and the half-decaying dose for the selenium XANES signal ranged from 5 to 43 MGy. These decay rates were 34- to 3.8-fold higher than the rate at which the Se atoms interacted directly with X-ray photons, so the damage mechanism must be a secondary effect. Samples that cooled to a more crystalline state generally decayed faster than samples that cooled to an amorphous solid. The single exception was a protein crystal where a nanocrystalline cryoprotectant had a protective effect. Lowering the pH, especially with ascorbic or nitric acids, had a protective effect, and SeMet lifetime increased monotonically with decreasing sample temperature (down to 93 K). The SeMet lifetime in one protein crystal was the same as that of the free amino acid, and the longest SeMet lifetime measured was found in the other protein crystal type. This protection was found to arise from the folded
Structural Origins of Nitroxide Side Chain Dynamics on Membrane Protein [alpha]-Helical Sites
Kroncke, Brett M.; Horanyi, Peter S.; Columbus, Linda
Understanding the structure and dynamics of membrane proteins in their native, hydrophobic environment is important to understanding how these proteins function. EPR spectroscopy in combination with site-directed spin labeling (SDSL) can measure dynamics and structure of membrane proteins in their native lipid environment; however, until now the dynamics measured have been qualitative due to limited knowledge of the nitroxide spin label's intramolecular motion in the hydrophobic environment. Although several studies have elucidated the structural origins of EPR line shapes of water-soluble proteins, EPR spectra of nitroxide spin-labeled proteins in detergents or lipids have characteristic differences from their water-soluble counterparts, suggesting significant differences in the underlying molecular motion of the spin label between the two environments. To elucidate these differences, membrane-exposed {alpha}-helical sites of the leucine transporter, LeuT, from Aquifex aeolicus, were investigated using X-ray crystallography, mutational analysis, nitroxide side chain derivatives, and spectral simulations in order to obtain a motional model of the nitroxide. For each crystal structure, the nitroxide ring of a disulfide-linked spin label side chain (R1) is resolved and makes contacts with hydrophobic residues on the protein surface. The spin label at site I204 on LeuT makes a nontraditional hydrogen bond with the ortho-hydrogen on its nearest neighbor F208, whereas the spin label at site F177 makes multiple van der Waals contacts with a hydrophobic pocket formed with an adjacent helix. These results coupled with the spectral effect of mutating the i {+-} 3, 4 residues suggest that the spin label has a greater affinity for its local protein environment in the low dielectric than on a water-soluble protein surface. The simulations of the EPR spectra presented here suggest the spin label oscillates about the terminal bond nearest the ring while maintaining weak contact
Influence of LC Content on the Phase Structures of Side-Chain Liquid
Tenneti, K.; Chen, X; Li, C; Shen, Z; Wan, X; Fan, X; Zhou, Q; Rong, L; Hsiao, B
We report the phase structures of a series of poly(styrene-block-{l_brace}3'-[4-(4-n-dodecyloxybenzoyloxy)benzoyloxy]-4-(12-methacryloyloxydodecyloxy)benzoyloxybiphenyl{r_brace}) (PS-b-PMAC) side-chain liquid crystalline block copolymers (SC LCBCP). The SC liquid crystalline polymer was formed by side attaching a bent-core mesogen to the polymer backbone using a 12-carbon spacer. The phase structure of the high and low fPMAC samples were investigated using differential scanning calorimetry, small-angle and wide-angle X-ray scattering, and transmission electron microscopy techniques. The PS coil block and PMAC LC block phase separate into a lamellar morphology in all of the samples investigated (volume fraction of PMAC fPMAC 0.31-0.65). However, both the LC phase and the orientation of the hierarchical structure under mechanical shear showed strong dependence on the LC content. Samples having a high fPMAC (0.5-0.65) showed a SmC2 LC phase (Smectic C denotes the LC molecules are tilted with respect to the layer normal, and 2 represents a bilayered structure), similar to that observed in PMAC homopolymers. Upon mechanical shear, these smectic layers oriented parallel to the shear plane and the BCP lamellae oriented perpendicular to the shear plane with the layer normal parallel to the vorticity direction. In samples having a lower fPMAC, the BCP lamellae laid parallel to the shear plane and the LC phase structure in these samples was columnar rectangular. A detailed structural and morphological study will be reported.
The Role of Short-Chain Conjugated Poly-(R)-3-Hydroxybutyrate (cPHB) in Protein Folding
Reusch, Rosetta N.
Poly-(R)-3-hydroxybutyrate (PHB), a linear polymer of R-3-hydroxybutyrate (R-3HB), is a fundamental constituent of biological cells. Certain prokaryotes accumulate PHB of very high molecular weight (10,000 to >1,000,000 residues), which is segregated within granular deposits in the cytoplasm; however, all prokaryotes and all eukaryotes synthesize PHB of medium-chain length (~100–200 residues) which resides within lipid bilayers or lipid vesicles, and PHB of short-chain length (<12 residues) which is conjugated to proteins (cPHB), primarily proteins in membranes and organelles. The physical properties of cPHB indicate it plays important roles in the targeting and folding of cPHB-proteins. Here we review the occurrence, physical properties and molecular characteristics of cPHB, and discuss its influence on the folding and structure of outer membrane protein A (OmpA) of Escherichia coli. PMID:23702844
Critical Roles of Hydrophobicity and Orientation of Side Chains for Inactivation of Sarcoplasmic Reticulum Ca2+-ATPase with Thapsigargin and Thapsigargin Analogs*
Winther, Anne-Marie L.; Liu, Huizhen; Sonntag, Yonathan; Olesen, Claus; le Maire, Marc; Soehoel, Helmer; Olsen, Carl-Erik; Christensen, S. Brøgger; Nissen, Poul; Møller, Jesper V.
Thapsigargin (Tg), a specific inhibitor of sarco/endoplasmic Ca2+-ATPases (SERCA), binds with high affinity to the E2 conformation of these ATPases. SERCA inhibition leads to elevated calcium levels in the cytoplasm, which in turn induces apoptosis. We present x-ray crystallographic and intrinsic fluorescence data to show how Tg and chemical analogs of the compound with modified or removed side chains bind to isolated SERCA 1a membranes. This occurs by uptake via the membrane lipid followed by insertion into a resident intramembranous binding site with few adaptative changes. Our binding data indicate that a balanced hydrophobicity and accurate positioning of the side chains, provided by the central guaianolide ring structure, defines a pharmacophore of Tg that governs both high affinity and access to the protein-binding site. Tg analogs substituted with long linkers at O-8 extend from the binding site between transmembrane segments to the putative N-terminal Ca2+ entry pathway. The long chain analogs provide a rational basis for the localization of the linker, the presence of which is necessary for enabling prostate-specific antigen to cleave peptide-conjugated prodrugs targeting SERCA of cancer cells (Denmeade, S. R., Jakobsen, C. M., Janssen, S., Khan, S. R., Garrett, E. S., Lilja, H., Christensen, S. B., and Isaacs, J. T. (2003) J. Natl. Cancer Inst. 95, 990–1000). Our study demonstrates the usefulness of a simple in vitro system to test and direct development toward the formulation of new Tg derivatives with improved properties for SERCA targeting. Finally, we propose that the Tg binding pocket may be a regulatory site that, for example, is sensitive to cholesterol. PMID:20551329
Simple physics-based analytical formulas for the potentials of mean force of the interaction of amino-acid side chains in water. VI. Oppositely-charged side chains
Makowski, Mariusz; Liwo, Adam; Scheraga, Harold A.
The two-site coarse-grained model for the interactions of charged side chains, to be used with our coarse-grained UNRES force field for protein simulations proposed in the accompanying paper, has been extended to pairs of oppositely-charged side chains. The potentials of mean force of four pairs of molecules modeling charged amino-acid side chains, i.e., propionate – n-pentylamine cation (for aspartic acid – lysine), butyrate…n-pentylamine cation (for glutamic acid – lysine), propionate –1-butylguanidine (for aspartic acid – arginine), and butyrate – 1-butylguanidine (for glutamic acid – arginine) pairs were determined by umbrella-sampling molecular dynamics simulations in explicit water as functions of distance and orientation, and the analytical expression was fitted to the potentials of mean force. Compared to pairs of like-charged side chains discussed in the accompanying paper, an average quadrupole-quadrupole interaction term had to be introduced to reproduce the Coulombic interactions, and a multi-state model of charge distribution had to be introduced to fit the potentials of mean force of all oppositely-charged pairs well. The model reproduces all salt-bridge minima and, consequently, is likely to improve the performance of the UNRES force field. PMID:21500791
Hydrogen-bonded side chain liquid crystalline block copolymer: Molecular design, synthesis, characterization and applications
NASA Astrophysics Data System (ADS)
Chao, Chi-Yang
Block copolymers can self-assemble into highly regular, microphase-separated morphologies with dimensions at nanometer length scales. Potential applications such as optical wavelength photonic crystals, templates for nanolithographic patterning, or nanochannels for biomacromolecular separation take advantage of the well-ordered, controlled size microdomains of block copolymers. Side-chain liquid crystalline block copolymers (SCLCBCPs) are drawing increasing attention since the incorporation of liquid crystallinity turns their well-organized microstructures into dynamic functional materials. As a special type of block copolymer, hydrogen-bonded SCLCBCPs are unique, compositionally tunable materials with multiple dynamic functionalities that can readily respond to thermal, electrical and mechanical fields. Hydrogen-bonded SCLCBCPs were synthesized and assembled from host poly(styrene- b-acrylic acid) diblock copolymers with narrow molecular weight distributions as proton donors and guest imidazole functionalized mesogenic moieties as proton acceptors. In these studies non-covalent hydrogen bonding is employed to connect mesogenic side groups to a block copolymer backbone, both for its dynamic character as well as for facile materials preparation. The homogeneity and configuration of the hydrogen-bonded complexes were determined by both the molecular architecture of imidazolyl side groups and the process conditions. A one-dimensional photonic crystal composed of high molecular weight hydrogen-bonded SCLCBCP, with temperature dependent optical wavelength stop bands was successfully produced. The microstructures of hydrogen-bonded complexes could be rapidly aligned in an AC electric field at temperatures below the order-disorder transition but above their glass transitions. Remarkable dipolar properties of the mesogenic groups and thermal dissociation of hydrogen bonds are key elements to fast orientation switching. Studies of a wide range of mesogen and polymer
Shear Flow Induced Transition from Liquid-Crystalline to Polymer Behavior in Side-Chain Liquid Crystal Polymers
NASA Astrophysics Data System (ADS)
Noirez, L.; Lapp, A.
We determine the structure and conformation of side-chain liquid-crystalline polymers subjected to shear flow in the vicinity of the smectic phase by neutron scattering on the velocity gradient plane. Below the nematic-smectic transition we observe a typical liquid-crystal behavior; the smectic layers slide, leading to a main-chain elongation parallel to the velocity direction. In contrast, a shear applied above the transition induces a tilted main-chain conformation which is typical for polymer behavior.
Accessibility, reactivity, and selectivity of side chains within a channel of de novo peptide assembly.
Burton, Antony J; Thomas, Franziska; Agnew, Christopher; Hudson, Kieran L; Halford, Stephen E; Brady, R Leo; Woolfson, Derek N
Ab initio design of enzymes requires precise and predictable positioning of reactive functional groups within accessible and controlled environments of de novo protein scaffolds. Here we show that multiple thiol moieties can be placed within a central channel, with approximate dimensions 6 × 42 Å, of a de novo, six-helix peptide assembly (CC-Hex). Layers of six cysteine residues are introduced at two different sites ~6 (the "L24C" mutant) and ~17 Å (L17C) from the C-terminal opening of the channel. X-ray crystal structures confirm the mutant structures as hexamers with internal free thiol, rather than disulfide-linked cysteine residues. Both mutants are hexa-alkylated upon addition of iodoacetamide, demonstrating accessibility and full reactivity of the thiol groups. Comparison of the alkylation and unfolding rates of the hexamers indicates that access is directly through the channel and not via dissociation and unfolding of the assembly. Moreover, neither mutant reacts with iodoacetic acid, demonstrating selectivity of the largely hydrophobic channel. These studies show that it is possible to engineer reactive side chains with both precision and control into a de novo scaffold to produce protein-like structures with chemoselective reactivity. PMID:23924058
Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.
Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio
Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. PMID:26213237
The effect of side-chain liquid crystalline concentration in liquid crystal on dielectric properties
NASA Astrophysics Data System (ADS)
Gökçen, M.; Köysal, O.; Yıldırım, M.; Altındal, Ş.
As liquid crystal (LC), E63 and as doping material, side-chain liquid crystalline polymer (SLCP) were used in this study. In order to observe the effect of SLCP concentration in LC on the dielectric properties in a wide range of frequency and bias voltage, SLCP was doped into E63 with 0 (pure E63), 1 and 10 wt%. The bias voltage and frequency dependence of the dielectric properties of pure E63 and doped mixtures (E63/SCLP) have been investigated using the admittance spectroscopy method (C-V and G/ω-V) in the frequency range of 10 kHz-10 MHz at room temperature. The values of dielectric constant (ɛ‧) and real (M‧) and imaginary (M″) parts of electric modulus of the pure E63 and E63/SLCP (1 and 10%) were calculated using the measured admittance values. Moreover, dielectric anisotropy (Δɛ) was also obtained for each sample as a function of frequency. Results show that the values of dielectric parameters are strong functions of frequency and applied bias voltage depending on the concentration amount. Furthermore, dielectric anisotropy has negative values according to p/n type changing for each sample after a critical frequency value.
Side-Chain Liquid Crystalline Poly(meth)acrylates with Bent-Core Mesogens
Chen,X.; Tenneti, K.; Li, C.; Bai, Y.; Wan, X.; Fan, X.; Zhou, Q.; Rong, L.; Hsiao, B.
We report the design, synthesis, and characterization of side-chain liquid crystalline (LC) poly(meth)acrylates with end-on bent-core liquid crystalline (BCLC) mesogens. Both conventional free radical polymerization and atom transfer radical polymerization have been used to synthesize these liquid crystalline polymers (LCP). The resulting polymers exhibit thermotropic LC behavior. Differential scanning calorimetry, thermopolarized light microscopy, wide-angle X-ray diffraction, and small-angle X-ray scattering were used to characterize the LC structure of both monomers and polymers. The electro-optic (EO) measurement was carried out by applying a triangular wave and measuring the LC EO response. SmCP (Smectic C indicates the LC molecules are tilted with respect to the layer normal; P denotes polar ordering) phases were observed for both monomers and polymers. In LC monomers, typical antiferroelectric switching was observed. In the ground state, SmCP{sub A} (A denotes antiferroelectric) was observed which switched to SmCP{sub F} (F denotes ferroelectric) upon applying an electric field. In the corresponding LCP, a unique bilayer structure was observed, which is different from the reported BCLC bilayer SmCG (G denotes generated) phase. Most of the LCPs did not switch upon applying electric field while weak AF switching was observed in a low molecular weight poly{l_brace}3'-[4-(4-n-dodecyloxybenzoyloxy)benzoyloxy]-4-(12-acryloyloxydodecyloxy)benzoyloxybiphenyl{r_brace} sample.
Poly(Amido Amine)s Containing Agmatine and Butanol Side Chains as Efficient Gene Carriers.
Won, Young-Wook; Ankoné, Marc; Engbersen, Johan F J; Feijen, Jan; Kim, Sung Wan
A new type of bioreducible poly(amido amine) copolymer is synthesized by the Michael addition polymerization of cystamine bisacrylamide (CBA) with 4-aminobutylguanidine (agmatine, AGM) and 4-aminobutanol (ABOL). Since the positively charged guanidinium groups of AGM and the hydroxybutyl groups of ABOL in the side chains have shown to improve the overall transfection efficiency of poly(amido amine)s, it is hypothesized that poly(CBA-ABOL/AGM) synthesized at the optimal ratio of both components would result in high transfection efficiency and minimal toxicity. In this study, a series of the poly(CBA-ABOL/AGM) copolymers is synthesized as gene carriers. The polymers are characterized and luciferase transfection efficiencies of the polymers in various cell lines are investigated to select the ideal ratio between AGM and ABOL. The poly(CBA-ABOL/AGM) containing 80% AGM and 20% ABOL has shown the best transfection efficiency with the lowest cytotoxicity, indicating that this polymer is very promising as a potent and nontoxic gene carrier. PMID:26663734
Protein Structure and Function: Looking through the Network of Side-Chain Interactions.
Bhattacharyya, Moitrayee; Ghosh, Soma; Vishveshwara, Saraswathi
Network theory has become an excellent method of choice through which biological data are smoothly integrated to gain insights into complex biological problems. Understanding protein structure, folding, and function has been an important problem, which is being extensively investigated by the network approach. Since the sequence uniquely determines the structure, this review focuses on the networks of non-covalently connected amino acid side chains in proteins. Questions in structural biology are addressed within the framework of such a formalism. While general applications are mentioned in this review, challenging problems which have demanded the attention of scientific community for a long time, such as allostery and protein folding, are considered in greater detail. Our aim has been to explore these important problems through the eyes of networks. Various methods of constructing protein structure networks (PSN) are consolidated. They include the methods based on geometry, edges weighted by different schemes, and also bipartite network of protein-nucleic acid complexes. A number of network metrics that elegantly capture the general features as well as specific features related to phenomena, such as allostery and protein model validation, are described. Additionally, an integration of network theory with ensembles of equilibrium structures of a single protein or that of a large number of structures from the data bank has been presented to perceive complex phenomena from network perspective. Finally, we discuss briefly the capabilities, limitations, and the scope for further explorations of protein structure networks. PMID:26412788
In Vitro Cytotoxicity of Benzopyranone Derivatives with Basic Side Chain Against Human Lung Cell Lines
Musa, Musiliyu A.; Badisa, Veera L.D.; Latinwo, Lekan M.; Waryoba, Caroline; Ugochukwu, Ngozi
Background Coumarins belong to an important group of useful drugs with diverse pharmacological properties. In the present study, the in vitro cytotoxicity of new coumarin-based benzopyranone derivatives containing diethylaminoethoxy (5), dimethylaminoethoxy (6), morpholinoethoxy (7), piperidinylethoxy (8) and pyrrolidinylethoxyl (9) amino side chain against human carcinoma (A549) and normal (LL47) lung cell lines was evaluated. Materials and Methods The cytotoxicity was evaluated by crystal violet dye binding assay. The effect of compound 9 on different phases of the cell cycle was determined using flow cytometry. Results In A549 cells, the 50% lethal dose (LD50) for compounds 5–9 were found to be 7.08, 5.0, 34.2, 8.33 and 5.83 µM, respectively, while in LL47 cells, the LD50 values were found to be 16.7, 20.4, 34.6, 15.4 and 8.75 µM, respectively after 48 h treatment. Cell cycle data indicated that A549 cells were arrested at different phases depending on the concentration. Conclusion Compounds 5–9 showed anticancer activity against lung cancer cell lines, while compound 6 showed highly selective anticancer activity. PMID:21115914
Backbone and side chain chemical shift assignments of apolipophorin III from Galleria mellonella.
Crowhurst, Karin A; Horn, James V C; Weers, Paul M M
Apolipophorin III, a 163 residue monomeric protein from the greater wax moth Galleria mellonella (abbreviated as apoLp-IIIGM), has roles in upregulating expression of antimicrobial proteins as well as binding and deforming bacterial membranes. Due to its similarity to vertebrate apolipoproteins there is interest in performing atomic resolution analysis of apoLp-IIIGM as part of an effort to better understand its mechanism of action in innate immunity. In the first step towards structural characterization of apoLp-IIIGM, 99 % of backbone and 88 % of side chain (1)H, (13)C and (15)N chemical shifts were assigned. TALOS+ analysis of the backbone resonances has predicted that the protein is composed of five long helices, which is consistent with the reported structures of apolipophorins from other insect species. The next stage in the characterization of apoLp-III from G. mellonella will be to utilize these resonance assignments in solving the solution structure of this protein. PMID:26493308
Tunable transport through a quantum dot chain with side-coupled Majorana bound states
Jiang, Cui; Lu, Gang; Gong, Wei-Jiang
We investigate the transport properties of a quantum dot (QD) chain side-coupled to a pair of Majorana bound states (MBSs). It is found that the zero-bias conductance is tightly dependent on the parity of QD number. First, if a Majorana zero mode is introduced to couple to one QD of the odd-numbered QD structure, the zero-bias conductance is equal to (e{sup 2})/(2h) , but the zero-bias conductance will experience a valley-to-peak transition if the Majorana zero mode couples to the different QDs of the even-numbered QD structure. On the other hand, when the inter-MBS coupling is nonzero, the zero-bias conductance spectrum shows a peak in the odd-numbered QD structure, and in the even-numbered QD structure one conductance valley appears at the zero-bias limit. These results show the feasibility to manipulate the current in a multi-QD structure based on the QD-MBS coupling. Also, such a system can be a candidate for detecting the MBSs.
Characterization of novel perylene diimides containing aromatic amino acid side chains.
Farooqi, Mohammed J; Penick, Mark A; Burch, Jessica; Negrete, George R; Brancaleon, Lorenzo
Perylene diimide derivatives have attracted initial interest as industrial dyes. Recently, much attention has been focused on their strong π-π stacks resulting from the large PDI aromatic core. These PDI stacks have distinct optical properties, and provide informative models that could mimic light-harvesting systems and initial charge transfer typical of photosynthetic systems. The absorption property of PDI derivatives may be tuned from visible to near-infrared region by peripheral substitution. We have studied a new class of PDI derivatives with aryl substituents derived from the side chains of aromatic aminoacids (Tyrosine, Tryptophan and Phenylalanine). We have investigated their absorption and the fluorescence properties in a set of organic solvents and established their different tendencies to aggregate in solution despite their solubility. Most aggregation appears to be unordered. One PDI analogue (the one formed from Tyr) in Methanol, however, appears to form J-type aggregates. Based on our results the compounds appear to be promising for future investigations regarding the interaction of these dyes with biomolecules. PMID:26298679
High-performance polymer semiconducting heterostructure devices by nitrene-mediated photocrosslinking of alkyl side chains.
Png, Rui-Qi; Chia, Perq-Jon; Tang, Jie-Cong; Liu, Bo; Sivaramakrishnan, Sankaran; Zhou, Mi; Khong, Siong-Hee; Chan, Hardy S O; Burroughes, Jeremy H; Chua, Lay-Lay; Friend, Richard H; Ho, Peter K H
Heterostructures are central to the efficient manipulation of charge carriers, excitons and photons for high-performance semiconductor devices. Although these can be formed by stepwise evaporation of molecular semiconductors, they are a considerable challenge for polymers owing to re-dissolution of the underlying layers. Here we demonstrate a simple and versatile photocrosslinking methodology based on sterically hindered bis(fluorophenyl azide)s. The photocrosslinking efficiency is high and dominated by alkyl side-chain insertion reactions, which do not degrade semiconductor properties. We demonstrate two new back-infiltrated and contiguous interpenetrating donor-acceptor heterostructures for photovoltaic applications that inherently overcome internal recombination losses by ensuring path continuity to give high carrier-collection efficiency. This provides the appropriate morphology for high-efficiency polymer-based photovoltaics. We also demonstrate photopatternable polymer-based field-effect transistors and light-emitting diodes, and highly efficient separate-confinement-heterostructure light-emitting diodes. These results open the way to the general development of high-performance polymer semiconductor heterostructures that have not previously been thought possible. PMID:19966791
Changes in cytochrome P450 side chain cleavage expression in the rat hippocampus after kainate injury.
Chia, Wan-Jie; Jenner, Andrew M; Farooqui, Akhlaq A; Ong, Wei-Yi
Our previous study showed an increase in total cholesterol level of the hippocampus after kainate-induced injury, but whether this is further metabolized to neurosteroids is not known. The first step in neurosteroid biosynthesis is the conversion of cholesterol to pregnenolone by the enzyme cytochrome P450 side chain cleavage (P450scc). This study was carried out to elucidate the expression of this enzyme in the kainate-lesioned rat hippocampus. A net decrease in P450scc protein was detected in hippocampal homogenates by Western blots at 2 weeks post-kainate injection (time of peak cholesterol concentration after kainate injury). Immunohistochemistry showed decreased labeling of the enzyme in neurons, but increased expression in a small number of astrocytes. The level of pregnenolone was also analyzed using a newly developed gas chromatography-mass spectrometry (GC-MS) method, optimized for the rat hippocampus. A non-significant tendency to a decrease in pregnenolone level was detected 2 weeks post-lesion. This is in contrast to a large increase in oxysterols in the lesioned hippocampus at this time (He et al. 2006). Together, they indicate that increased cholesterol in the kainate lesioned hippocampus is mostly metabolized to oxysterols, and not neurosteroids. PMID:18040670
Simple physics-based analytical formulas for the potentials of mean force of the interaction of amino-acid side chains in water. V. Like-charged side chains.
Makowski, Mariusz; Liwo, Adam; Sobolewski, Emil; Scheraga, Harold A
A new model of side-chain-side-chain interactions for charged side-chains of amino acids, to be used in the UNRES force-field, has been developed, in which a side chain consists of a nonpolar and a charged site. The interaction energy between the nonpolar sites is composed of a Gay-Berne and a cavity term; the interaction energy between the charged sites consists of a Lennard-Jones term, a Coulombic term, a generalized-Born term, and a cavity term, while the interaction energy between the nonpolar and charged sites is composed of a Gay-Berne and a polarization term. We parametrized the energy function for the models of all six pairs of natural like-charged amino-acid side chains, namely propionate-propionate (for the aspartic acid-aspartic acid pair), butyrate-butyrate (for the glutamic acid-glutamic acid pair), propionate-butyrate (for the aspartic acid-glutamic acid pair), pentylamine cation-pentylamine cation (for the lysine-lysine pair), 1-butylguanidine cation-1-butylguanidine cation (for the arginine-arginine pair), and pentylamine cation-1-butylguanidine cation (for the lysine-arginine pair). By using umbrella-sampling molecular dynamics simulations in explicit TIP3P water, we determined the potentials of mean force of the above-mentioned pairs as functions of distance and orientation and fitted analytical expressions to them. The positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the orientation of the molecules were well represented by analytical expressions for all systems. The values of the parameters of all the energy components are physically reasonable, which justifies use of such potentials in coarse-grain protein-folding simulations. PMID:21500792
Simple physics-based analytical formulas for the potentials of mean force of the interaction of amino-acid side chains in water. V. Like-charged side chains
Makowski, Mariusz; Liwo, Adam; Sobolewski, Emil; Scheraga, Harold A.
A new model of side-chain – side-chain interactions for charged side-chains of amino acids, to be used in the UNRES force-field, has been developed, in which a side chain consists of a nonpolar and a charged site. The interaction energy between the nonpolar sites is composed of a Gay-Berne and a cavity term; the interaction energy between the charged sites consists of a Lennard-Jones term, a Coulombic term, a Generalized-Born term, and a cavity term, while the interaction energy between the nonpolar and charged sites is composed of a Gay-Berne and a polarization term. We parameterized the energy function for the models of all six pairs of natural like-charged amino-acid side chains, namely propionate-propionate (for the aspartic acid-aspartic acid pair), butyrate-butyrate (for the glutamic acid-glutamic acid pair), propionate-butyrate (for the aspartic acid-glutamic acid pair), pentylamine cation-pentylamine cation (for the lysine-lysine pair), 1-butylguanidine cation-1-butylguanidine cation (for the arginine-arginine pair), and pentylamine cation-1-butylguanidine cation (for the lysine-arginine pair). By using umbrella-sampling molecular dynamics simulations in explicit TIP3P water, we determined the potentials of mean force of the above-mentioned pairs as functions of distance and orientation and fitted analytical expressions to them. The positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the orientation of the molecules were well represented by analytical expressions for all systems. The values of the parameters of all the energy components are physically reasonable, which justifies use of such potentials in coarse-grain protein-folding simulations. PMID:21500792
Copper(I)-catalyzed azide-alkyne cycloaddition for the synthesis of nonlinear electro-optic side-chain copolymers
NASA Astrophysics Data System (ADS)
Galindo, Christophe; Soyer, Françoise; Le Barny, Pierre
The Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) has been investigated as a versatile synthetic pathway to graft highly chemically sensitive "push-pull" chromophores onto a polymer backbone. We demonstrate that the CuAAC is highly efficient in mild conditions, chemioselective and is a powerful tool to design new powerful organic NLO side-chain copolymers.
Synthesis and antiviral activity evaluation of acyclic 2'-azanucleosides bearing a phosphonomethoxy function in the side chain.
Koszytkowska-Stawińska, Mariola; De Clercq, Erik; Balzarini, Jan
Acyclic 2'-azanucleosides with a phosphonomethoxy function in the side chain were obtained by coupling of diethyl {2-[N-(pivaloyloxymethyl)-N-(p-toluenesulfonyl)amino]ethoxymethyl}phosphonate with the pyrimidine nucleobases via the Vorbrüggen-type protocol. The compounds were evaluated in vitro for activity against a broad variety of RNA and DNA viruses. PMID:19442526
The Relationship of Pretilt Angle and Chemical Structure of Rubbed Organo-Soluble Side-Chain Polyimides
NASA Astrophysics Data System (ADS)
Mann, Ian K.; Bai, F.; Bai, Z.; Ge, J.; Sun, L.; Wang, H.; Zhang, Z.; Harris, Frank W.; Cheng, Stephen Z. D.
This work is concerned with the relationship between the properties of the pretilt angles and chemical structure of the alignment layer for a series of novel organo-soluble side-chain polyimides developed at The University of Akron. The polyimides were spin cast on ITO glass substrates and mechanically rubbed with a velvet cloth. Liquid crystal display cells were constructed with an anti-parallel geometry using 10μm glass spacers and filled with the nematic liquid crystal mixture E7. The pretilt angle, which is defined as the angle between the liquid crystal director and the substrate, was measured using the magnetic null method. Various side-chain polyimide films were prepared and pretilt angles were determined employing identical processing conditions. In general, polyimides containing long flexible aliphatic side-chains (no. carbons >12) resulted in high pretilt angles (>20^o) however over time the pretilt shifted to a homeotropic alignment (i.e. 90^o to the substrate). The stability of the pretilt angles was improved when polyimide copolymers were used. Further enhancement of the stability was achieved by crosslinking the system prior to rubbing. Liquid crystal like side-chains (cyanobiphenol and biphenol based) resulted in stable pretilt angles ranging from 20 to 40^o for a spacer length of six carbons. Several surface techniques were used to study the effect of rubbing, including; atomic force microscopy, surfaced enhanced Raman scattering, and contact angle.
Homeotropically-aligned main-chain and side-on liquid crystalline elastomer films with high anisotropic thermal conductivities.
Wang, Meng; Wang, Jun; Yang, Hong; Lin, Bao-Ping; Chen, Er-Qiang; Keller, Patrick; Zhang, Xue-Qin; Sun, Ying
Homeotropically-aligned main-chain and side-on liquid crystalline elastomer films are prepared by using LC thiol-ene and acrylate systems respectively. Evaluated by laser flash analysis, the room temperature thermal conductivities of these two LCP films in the film normal direction are both dramatically higher than those along the horizontal direction. PMID:26960421
Tuning cation-binding selectivity and capacity via side chain-dependent molecular packing in the solid state.
Shen, Jie; Ren, Changliang; Zeng, Huaqiang
Cavity-containing cation-binding pentameric macrocycles readily assemble, via side chain-dependent molecular packing, into either 1D nanotube bundles with the smallest being 10 nm in diameter or nanoplates of different sizes. The resultant nanostructures are able to selectively remove metal salts from aqueous solutions with varying selectivities and capacities. PMID:27476578
Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells☆
Garay, Edward; Jankowski, Pawel; Lizano, Paulo; Marczak, Stanislaw; Maehr, Hubert; Adorini, Luciano; Uskokovic, Milan R.; Studzinski, George P.
Signaling of cell differentiation is one of the important physiological functions of the activated vitamin D receptor (VDR). Activation of the VDR can be achieved not only by 1α,25-dihydroxyvitamin D3 (1,25D), the natural ligand, but also by a large number of its analogs. These include a category containing two side chains emanating at C-20, generally referred to as Gemini. The introduction of a cyclopropyl moiety as part of the pro-R side chain provides modified Gemini compounds with increased steric requirement and decreased chain flexibility; the biological consequences of this novel structural variant are subject of this investigation. In general, the resulting 1α,25-dihydroxy-(4-hydroxy-4-methyl-pentyl)-21,22-cis-cyclo-cholecalciferols reduced had differentiation and transcriptional potency and induced cell cycle arrest less effciently, as shown by a decrease in G1/S ratio, when compared to 1,25D. Modifying their calcitriol side chain in the form of a 4-hydroxy-4-trifluoromethyl-5,5,5-trifluoropent-2-ynyl moiety, however, resulted in pronounced induction of differentiation in 1,25D-sensitive and moderate level of differentiation in 1,25D-resistant leukemia cells. PMID:17485214
Main chain and side chain dynamics of a heme protein: 15N and 2H NMR relaxation studies of R. capsulatus ferrocytochrome c2.
Flynn, P F; Bieber Urbauer, R J; Zhang, H; Lee, A L; Wand, A J
A detailed characterization of the main chain and side chain dynamics in R. capsulatus ferrocytochrome c(2) derived from (2)H NMR relaxation of methyl group resonances is presented. (15)N relaxation measurements confirm earlier results indicating that R. capsulatus ferrocytochrome c(2) exhibits minor rotational anisotropy in solution. The current study is focused on the use of deuterium relaxation in side chain methyl groups, which has been shown to provide a detailed and accurate measure of internal dynamics. Results obtained indicate that the side chains of ferrocytochrome c(2) exhibit a wide range of motional amplitudes, but are more rigid than generally found in the interior of nonprosthetic group bearing globular proteins. This unusual rigidity is ascribed to the interactions of the protein with the large heme prosthetic group. This observation has significant implications for the potential of the heme-protein interface to modulate the redox properties of the protein and also points to the need for great precision in the design and engineering of heme proteins. PMID:11380250
Extension of microwave-accelerated residue-specific acid cleavage to proteins with carbohydrate side chains and disulfide linkages
NASA Astrophysics Data System (ADS)
Li, Jinxi; Shefcheck, Kevin; Callahan, John; Fenselau, Catherine
This laboratory has introduced a chemical method for residue-specific protein cleavage and has provided a preliminary assessment of the suitability of microwave-accelerated acid cleavage as a proteomic tool. This report is a continuing assessment of the fate of common protein modifications in microwave-accelerated acid cleavage. We have examined the cleavage of ribonuclease A and the related N-linked glycoprotein ribonuclease B, and the O-linked glycoprotein alpha crystallin A chain, using MALDI-TOF and LC-ESI-MS to identify the peptide products. RNase A and B each contains four disulfide bonds, and the addition of a reducing reagent, such as dithiothreitol, was found to be required to achieve efficient acidic proteolysis. The linkage of the glycosidic group to the asparagine side chain in ribonuclease B was found not to be cleaved by brief microwave treatment in 12.5% acetic acid. The distribution of the heterogeneous carbohydrate side chain in the glycopeptide products of acid cleavage was compared to that of the glycopeptide products of tryptic digestion. Hydrolysis within the carbohydrate chain itself is minimal under the conditions used. The O-linked side chain on alpha crystalline A was found to be cleaved during acid cleavage of the protein.
Isotridecanyl side chain of plusbacin-A3 is essential for the transglycosylase inhibition of peptidoglycan biosynthesis§
Kim, Sung Joon; Singh, Manmilan; Wohlrab, Aaron; Yu, Tsyr-Yan; Patti, Gary J.; O'Connor, Robert D.; VanNieuwenhze, Michael; Schaefer, Jacob
Plusbacin-A3 (pb-A3) is a cyclic lipodepsipeptide which exhibits antibacterial activity against multidrug-resistant Gram-positive pathogens. Plusbacin-A3 is thought not to enter the cell cytoplasm and its lipophilic isotridecanyl side chain is presumed to insert into the membrane bilayer thereby facilitating either lipid II binding or some form of membrane disruption. Analogues of pb-A3, [2H]pb-A3 and deslipo-pb-A3, were synthesized to test membrane insertion as key to the mode of action. [2H]pb-A3 has a 2H-isotopically labeled isopropyl subunit of the lipid side chain, and deslipo-pb-A3 is missing the isotridecanyl side chain. Both analogues have the pb-A3 core structure. The loss of antimicrobial activity in deslipo-pb-A3 showed that the isotridecanyl side chain is crucial for the drug mode of action. However, rotational-echo double resonance NMR characterization of [2H]pb-A3 bound to [1-13C]glycine labeled whole-cells of Staphylococcus aureus showed that the isotridecanyl side chain does not insert into the lipid membrane, but instead is found in the staphylococcal cell wall, positioned near the pentaglycyl cross-bridge of the cell-wall peptidoglycan. Addition of [2H]pb-A3 during S. aureus growth resulted in an accumulation of Park's nucleotide, consistent with the inhibition of the transglycosylation step of peptidoglycan biosynthesis. PMID:23421534
Amphiphilic Surface Active Triblock Copolymers with Mixed Hydrophobic and Hydrophilic Side Chains for Tuned Marine Fouling-Release Properties
Park, D.; Weinman, C; Finlay, J; Fletcher, B; Paik, M; Sundaram, H; Dimitriou, M; Sohn, K; Callow, M; et al.
Two series of amphiphilic triblock surface active block copolymers (SABCs) were prepared through chemical modification of two polystyrene-block-poly(ethylene-ran-butylene)-block-polyisoprene ABC triblock copolymer precursors. The methyl ether of poly(ethylene glycol) [M{sub n} {approx} 550 g/mol (PEG550)] and a semifluorinated alcohol (CF{sub 3}(CF{sub 2}){sub 9}(CH{sub 2}){sub 10}OH) [F10H10] were attached at different molar ratios to impart both hydrophobic and hydrophilic groups to the isoprene segment. Coatings on glass slides consisting of a thin layer of the amphiphilic SABC deposited on a thicker layer of an ABA polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene thermoplastic elastomer were prepared for biofouling assays with algae. Dynamic water contact angle analysis, X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS) measurements were utilized to characterize the surfaces. Clear differences in surface structure were realized as the composition of attached side chains was varied. In biofouling assays, the settlement (attachment) of zoospores of the green alga Ulva was higher for surfaces incorporating a large proportion of the hydrophobic F10H10 side chains, while surfaces with a large proportion of the PEG550 side chains inhibited settlement. The trend in attachment strength of sporelings (young plants) of Ulva did not show such an obvious pattern. However, amphiphilic SABCs incorporating a mixture of PEG550 and F10H10 side chains performed the best. The number of cells of the diatom Navicula attached after exposure to flow decreased as the content of PEG550 to F10H10 side chains increased.
Adapting Poisson-Boltzmann to the self-consistent mean field theory: Application to protein side-chain modeling
NASA Astrophysics Data System (ADS)
Koehl, Patrice; Orland, Henri; Delarue, Marc
We present an extension of the self-consistent mean field theory for protein side-chain modeling in which solvation effects are included based on the Poisson-Boltzmann (PB) theory. In this approach, the protein is represented with multiple copies of its side chains. Each copy is assigned a weight that is refined iteratively based on the mean field energy generated by the rest of the protein, until self-consistency is reached. At each cycle, the variational free energy of the multi-copy system is computed; this free energy includes the internal energy of the protein that accounts for vdW and electrostatics interactions and a solvation free energy term that is computed using the PB equation. The method converges in only a few cycles and takes only minutes of central processing unit time on a commodity personal computer. The predicted conformation of each residue is then set to be its copy with the highest weight after convergence. We have tested this method on a database of hundred highly refined NMR structures to circumvent the problems of crystal packing inherent to x-ray structures. The use of the PB-derived solvation free energy significantly improves prediction accuracy for surface side chains. For example, the prediction accuracies for χ1 for surface cysteine, serine, and threonine residues improve from 68%, 35%, and 43% to 80%, 53%, and 57%, respectively. A comparison with other side-chain prediction algorithms demonstrates that our approach is consistently better in predicting the conformations of exposed side chains.
Hydrogen bonding motifs of protein side chains: descriptions of binding of arginine and amide groups.
Shimoni, L.; Glusker, J. P.
The modes of hydrogen bonding of arginine, asparagine, and glutamine side chains and of urea have been examined in small-molecule crystal structures in the Cambridge Structural Database and in crystal structures of protein-nucleic acid and protein-protein complexes. Analysis of the hydrogen bonding patterns of each by graph-set theory shows three patterns of rings (R) with one or two hydrogen bond acceptors and two donors and with eight, nine, or six atoms in the ring, designated R2(2)(8), R2(2)(9), and R1(2)(6). These three patterns are found for arginine-like groups and for urea, whereas only the first two patterns R2(2)(8) and R2(2)(9) are found for asparagine- and glutamine-like groups. In each case, the entire system is planar within 0.7 A or less. On the other hand, in macromolecular crystal structures, the hydrogen bonding patterns in protein-nucleic acid complexes between the nucleic acid base and the protein are all R2(2)(9), whereas hydrogen bonding between Watson-Crick-like pairs of nucleic acid bases is R2(2)(8). These two hydrogen bonding arrangements [R2(2)(9)] and R2(2)(8)] are predetermined by the nature of the groups available for hydrogen bonding. The third motif identified, R1(2)(6), involves hydrogen bonds that are less linear than in the other two motifs and is found in proteins. PMID:7773178
Polymer gels with associating side chains and their interaction with surfactants
NASA Astrophysics Data System (ADS)
Gordievskaya, Yulia D.; Rumyantsev, Artem M.; Kramarenko, Elena Yu.
Conformational behaviour of hydrophobically modified (HM) polymer gels in solutions of nonionic surfactants is studied theoretically. A HM gel contains hydrophobic side chains (stickers) grafted to its subchains. Hydrophobic stickers are capable to aggregate into joint micelles with surfactant molecules. Micelles containing more than one sticker serve as additional physical cross-links of the network, and their formation causes gel shrinking. In the proposed theoretical model, the interior of the gel/surfactant complex is treated as an array of densely packed spherical polymer brushes consisting of gel subchains tethered to the surface of the spherical sticker/surfactant micelles. Effect of stickers length and grafting density, surfactant concentration and hydrophobicity on gel swelling as well as on hydrophobic association inside it is analyzed. It is shown that increasing surfactant concentration can result in a gel collapse, which is caused by surfactant-induced hydrophobic aggregation of stickers, and a successive gel reswelling. The latter should be attributed to a growing fraction of surfactants in joint aggregates and, hence, increasing number of micelles containing only one sticker and not participating in gel physical cross-linking. In polyelectrolyte (PE) gels hydrophobic aggregation is opposed by osmotic pressure of mobile counterions, so that at some critical ionization degree hydrophobic association is completely suppressed. Hydrophobic modification of polymers is shown to open new ways for controlling gel responsiveness. In particular, it is discussed that incorporation of photosensitive groups into gel subchains and/or surfactant tail could give a possibility to vary the gel volume by light. Since hydrophobic aggregation regularities in gels and solutions are common, we hope our findings will be useful for design of polymer based self-healing materials as well.
Polymer gels with associating side chains and their interaction with surfactants.
Gordievskaya, Yulia D; Rumyantsev, Artem M; Kramarenko, Elena Yu
Conformational behaviour of hydrophobically modified (HM) polymer gels in solutions of nonionic surfactants is studied theoretically. A HM gel contains hydrophobic side chains (stickers) grafted to its subchains. Hydrophobic stickers are capable to aggregate into joint micelles with surfactant molecules. Micelles containing more than one sticker serve as additional physical cross-links of the network, and their formation causes gel shrinking. In the proposed theoretical model, the interior of the gel/surfactant complex is treated as an array of densely packed spherical polymer brushes consisting of gel subchains tethered to the surface of the spherical sticker/surfactant micelles. Effect of stickers length and grafting density, surfactant concentration and hydrophobicity on gel swelling as well as on hydrophobic association inside it is analyzed. It is shown that increasing surfactant concentration can result in a gel collapse, which is caused by surfactant-induced hydrophobic aggregation of stickers, and a successive gel reswelling. The latter should be attributed to a growing fraction of surfactants in joint aggregates and, hence, increasing number of micelles containing only one sticker and not participating in gel physical cross-linking. In polyelectrolyte (PE) gels hydrophobic aggregation is opposed by osmotic pressure of mobile counterions, so that at some critical ionization degree hydrophobic association is completely suppressed. Hydrophobic modification of polymers is shown to open new ways for controlling gel responsiveness. In particular, it is discussed that incorporation of photosensitive groups into gel subchains and/or surfactant tail could give a possibility to vary the gel volume by light. Since hydrophobic aggregation regularities in gels and solutions are common, we hope our findings will be useful for design of polymer based self-healing materials as well. PMID:27179504
Shear mechanical anisotropy of side chain liquid-crystal elastomers: Influence of sample preparation
NASA Astrophysics Data System (ADS)
Rogez, D.; Francius, G.; Finkelmann, H.; Martinoty, P.
We study the mechanical anisotropy of a series of uniaxial side chain nematic elastomers prepared with the same chemical composition but with different preparation protocols. For all the compounds, the experiments performed as a function of temperature show no discontinuity in both G'// and G'⊥ (the labels // and ⊥ stand for the director parallel, respectively perpendicular to the shear displacement) around the nematic-isotropic (N-I) phase transition temperature determined by DSC. They also all show a small decrease in G'// starting at temperatures well above this temperature (from ˜ 4°C to ˜ 20°C depending on the compound studied) and leading to a small hydrodynamic value of the G'⊥/G'// ratio. The measurements taken as a function of frequency show that the second plateau in G'// and the associated dip in G//" expected from dynamic semi-soft elasticity are not observed. These results can be described by the de Gennes model, which predicts small elastic anisotropy in the hydrodynamic and linear regimes. They correspond to the behavior expected for compounds beyond the mechanical critical point, which is consistent with the NMR and specific heat measurements taken on similar compounds. We also show that a reduction in the cross-linking density does not change the non-soft character of the mechanical response. From the measurements taken as a function of frequency at several temperatures we deduce that the time-temperature superposition method does not apply. From these measurements, we also determine the temperature dependence of the longest relaxation time τE of the network for the situations where the director is either parallel or perpendicular to the shear velocity. Finally, we discuss the influence on the measurements of the mechanical constraint associated with the fact that the samples cannot change their shape around the pseudo phase transition, because of their strong adherence on the sample-bearing glass slides.
Hydrogen-bonding studies of amino acid side-chains with DNA base pairs
NASA Astrophysics Data System (ADS)
Deepa, P.; Kolandaivel, P.; Senthilkumar, K.
The interactions of the amino acid side-chains arginine (ARG), aspartic acid (ASP), asparagine (ASN), lysine (LYS) and serine (SER) with nucleic acid base pairs have been investigated using theoretical methods. The interaction energy of the short intermolecular N-H ... N, N-H ... O, O-H ... O, O-H ... N, C-H ... O and C-H ... N hydrogen bonds present in both isolated base pairs and complexes and its role in providing stability to the complexes have been explored. The homonuclear interactions are found to be stronger than the heteronuclear interactions. An improper hydrogen bond has been observed for some of the N-H ... O and N-H ... N hydrogen-bond interactions with the contraction of the N-H bond varying from 0.001 to 0.0260 Å and the corresponding blue shift of the stretching frequency by 4-291 cm-1. Localized molecular orbital energy decomposition analysis (LMOEDA) reveals that the major contributions to the energetics are from the long-range polarization (PL) interaction, and the short-range attractive (ES, EX) and repulsive (REP) interactions. The Bader's atoms in molecules (AIM) theory shows good correlation for the electron density and its Laplacian at the bond critical points (BCP) with the N-H ... N and N-H ... O hydrogen-bond lengths in the complexes, and gives a proper explanation for the stability of the structure. The charge-transfer from the proton acceptor to the antibonding orbital of the X-H bond in the complexes was studied using natural bond orbital (NBO) analysis.
Shear mechanical anisotropy of side chain liquid-crystal elastomers: influence of sample preparation.
Rogez, D; Francius, G; Finkelmann, H; Martinoty, P
We study the mechanical anisotropy of a series of uniaxial side chain nematic elastomers prepared with the same chemical composition but with different preparation protocols. For all the compounds, the experiments performed as a function of temperature show no discontinuity in both G' (//) and G' ( perpendicular) (the labels // and perpendicular stand for the director parallel, respectively perpendicular to the shear displacement) around the nematic-isotropic (N-I) phase transition temperature determined by DSC. They also all show a small decrease in G' (//) starting at temperatures well above this temperature (from approximately 4( degrees ) C to approximately 20( degrees ) C depending on the compound studied) and leading to a small hydrodynamic value of the G' ( perpendicular)/G' (//) ratio. The measurements taken as a function of frequency show that the second plateau in G' (//) and the associated dip in G (//)" expected from dynamic semi-soft elasticity are not observed. These results can be described by the de Gennes model, which predicts small elastic anisotropy in the hydrodynamic and linear regimes. They correspond to the behavior expected for compounds beyond the mechanical critical point, which is consistent with the NMR and specific heat measurements taken on similar compounds. We also show that a reduction in the cross-linking density does not change the non-soft character of the mechanical response. From the measurements taken as a function of frequency at several temperatures we deduce that the time-temperature superposition method does not apply. From these measurements, we also determine the temperature dependence of the longest relaxation time tau(E) of the network for the situations where the director is either parallel or perpendicular to the shear velocity. Finally, we discuss the influence on the measurements of the mechanical constraint associated with the fact that the samples cannot change their shape around the pseudo phase transition
The glass transition of polymers with different side-chain stiffness confined in free-standing thin films
NASA Astrophysics Data System (ADS)
Xie, Shi-Jie; Qian, Hu-Jun; Lu, Zhong-Yuan
The effect of confinement on the glass transition temperature Tg of polymeric glass formers with different side chain stiffness is investigated by coarse-grained molecular dynamics simulations. We find that polymer with stiffer side groups exhibits much more pronounced Tg variation in confinement compared to that with relatively flexible side groups, in good agreement with experiments. Our string analysis demonstrates that the polymer species dependence of dynamics can be described by an Adam-Gibbs like relation between the size of cooperatively rearranging regions and relaxation time. However, the primary effect of changing side-group stiffness is to alter the activation barrier for rearrangement, rather than string size. We clarify that free-surface perturbation is the primary factor in determining the magnitude of Tg variation for polymers in confinement: It is more significant for polymers having higher Tg and results in much more pronounced reduction of surface Tg and then the overall Tg of the polymers.
The Inherent Conformational Preferences of Glutamine-Containing Peptides: the Role for Side-Chain Backbone Hydrogen Bonds
NASA Astrophysics Data System (ADS)
Walsh, Patrick S.; McBurney, Carl; Gellman, Samuel H.; Zwier, Timothy S.
Glutamine is widely known to be found in critical regions of peptides which readily fold into amyloid fibrils, the structures commonly associated with Alzheimer's disease and glutamine repeat diseases such as Huntington's disease. Building on previous single-conformation data on Gln-containing peptides containing an aromatic cap on the N-terminus (Z-Gln-OH and Z-Gln-NHMe), we present here single-conformation UV and IR spectra of Ac-Gln-NHBn and Ac-Ala-Gln-NHBn, with its C-terminal benzyl cap. These results point towards side-chain to backbone hydrogen bonds dominating the structures observed in the cold, isolated environment of a molecular beam. We have identified and assigned three main conformers for Ac-Gln-NHBn all involving primary side-chain to backbone interactions. Ac-Ala-Gln-NHBn extends the peptide chain by one amino acid, but affords an improvement in the conformational flexibility. Despite this increase in the flexibility, only a single conformation is observed in the gas-phase: a structure which makes use of both side-chain-to-backbone and backbone-to-backbone hydrogen bonds.
Two different pathways of internal conversion in carotenoids depending on the length of the conjugated chain
NASA Astrophysics Data System (ADS)
Fujii, Ritsuko; Inaba, Toru; Watanabe, Yasutaka; Koyama, Yasushi; Zhang, Jian-Ping
Near-infrared, subpicosecond time-resolved absorption spectroscopy of all- trans carotenoids having the number of conjugated double bonds, n=9-13, identified two different pathways of internal conversion in accordance with the energy diagram recently determined by measurements of resonance-Raman excitation profiles (RREPs) [K. Furuichi, T. Sashima, Y. Koyama, Chem. Phys. Lett. 356 (2002) 547]: the 1B u+→1B u-→2A g- internal conversion for neurosporene ( n=9) and spheroidene ( n=10), whereas the 1B u+→3A g-→2A g- internal conversion for lycopene ( n=11), anhydrorhodovibrin ( n=12) and spirilloxanthin ( n=13).
Structure-Function Studies of Hydrophobic Residues That Clamp a Basic Glutamate Side Chain during Catalysis by Triosephosphate Isomerase.
Richard, John P; Amyes, Tina L; Malabanan, M Merced; Zhai, Xiang; Kim, Kalvin J; Reinhardt, Christopher J; Wierenga, Rik K; Drake, Eric J; Gulick, Andrew M
Kinetic parameters are reported for the reactions of whole substrates (kcat/Km, M(-1) s(-1)) (R)-glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP) and for the substrate pieces [(kcat/Km)E·HPi/Kd, M(-2) s(-1)] glycolaldehyde (GA) and phosphite dianion (HPi) catalyzed by the I172A/L232A mutant of triosephosphate isomerase from Trypanosoma brucei brucei (TbbTIM). A comparison with the corresponding parameters for wild-type, I172A, and L232A TbbTIM-catalyzed reactions shows that the effect of I172A and L232A mutations on ΔG(⧧) for the wild-type TbbTIM-catalyzed reactions of the substrate pieces is nearly the same as the effect of the same mutations on TbbTIM previously mutated at the second side chain. This provides strong evidence that mutation of the first hydrophobic side chain does not affect the functioning of the second side chain in catalysis of the reactions of the substrate pieces. By contrast, the effects of I172A and L232A mutations on ΔG(⧧) for wild-type TbbTIM-catalyzed reactions of the whole substrate are different from the effect of the same mutations on TbbTIM previously mutated at the second side chain. This is due to the change in the rate-determining step that determines the barrier to the isomerization reaction. X-ray crystal structures are reported for I172A, L232A, and I172A/L232A TIMs and for the complexes of these mutants to the intermediate analogue phosphoglycolate (PGA). The structures of the PGA complexes with wild-type and mutant enzymes are nearly superimposable, except that the space opened by replacement of the hydrophobic side chain is occupied by a water molecule that lies ∼3.5 Å from the basic side chain of Glu167. The new water at I172A mutant TbbTIM provides a simple rationalization for the increase in the activation barrier ΔG(⧧) observed for mutant enzyme-catalyzed reactions of the whole substrate and substrate pieces. By contrast, the new water at the L232A mutant does not predict the decrease in
Solvation free energies of amino acid side chain analogs for common molecular mechanics water models
NASA Astrophysics Data System (ADS)
Shirts, Michael R.; Pande, Vijay S.
Quantitative free energy computation involves both using a model that is sufficiently faithful to the experimental system under study (accuracy) and establishing statistically meaningful measures of the uncertainties resulting from finite sampling (precision). In order to examine the accuracy of a range of common water models used for protein simulation for their solute/solvent properties, we calculate the free energy of hydration of 15 amino acid side chain analogs derived from the OPLS-AA parameter set with the TIP3P, TIP4P, SPC, SPC/E, TIP3P-MOD, and TIP4P-Ew water models. We achieve a high degree of statistical precision in our simulations, obtaining uncertainties for the free energy of hydration of 0.02-0.06kcal/mol, equivalent to that obtained in experimental hydration free energy measurements of the same molecules. We find that TIP3P-MOD, a model designed to give improved free energy of hydration for methane, gives uniformly the closest match to experiment; we also find that the ability to accurately model pure water properties does not necessarily predict ability to predict solute/solvent behavior. We also evaluate the free energies of a number of novel modifications of TIP3P designed as a proof of concept that it is possible to obtain much better solute/solvent free energetic behavior without substantially negatively affecting pure water properties. We decrease the average error to zero while reducing the root mean square error below that of any of the published water models, with measured liquid water properties remaining almost constant with respect to our perturbations. This demonstrates there is still both room for improvement within current fixed-charge biomolecular force fields and significant parameter flexibility to make these improvements. Recent research in computational efficiency of free energy methods allows us to perform simulations on a local cluster that previously required large scale distributed computing, performing four times as much
Tuning Structural and Mechanical Properties of Two-Dimensional Molecular Crystals: The Roles of Carbon Side Chains
Cun, Huanyao; Wang, Yeliang; Du, S X; Zhang, Lei; Zhang, Lizhi; Yang, Bing; He, Xiaobo; Wang, Yue; Zhu, Xueyan; Yuan, Quanzi; Zhao, Ya-Pu; Ouyang, Min; Hofer, Werner A.; Pennycook, Stephen J; Gao, Hong-jun
A key requirement for the future applicability of molecular electronics devices is a resilience of their properties to mechanical deformation. At present, however, there is no fundamental understanding of the origins of mechanical properties of molecular films. Here we use quinacridone, which possesses flexible carbon side chains, as a model molecular system to address this issue. Eight molecular configurations with different molecular coverage are identified by scanning tunneling microscopy. Theoretical calculations reveal quantitatively the roles of different molecule-molecule and molecule-substrate interactions and predict the observed sequence of configurations. Remarkably, we find that a single Young's modulus applies for all configurations, the magnitude of which is controlled by side chain length, suggesting a versatile avenue for tuning not only the physical and chemical properties of molecular films but also their elastic properties.
Synthesis, characterization and antitumor activities of some steroidal derivatives with side chain of 17-hydrazone aromatic heterocycle.
Cui, Jianguo; Liu, Liang; Zhao, Dandan; Gan, Chunfang; Huang, Xin; Xiao, Qi; Qi, Binbin; Yang, Lei; Huang, Yanmin
Here a series of dehydroepiandrosterone-17-hydrazone and estrone-17-hydrazone derivatives possessing various aromatic heterocycle structures in 17-side chain of their steroidal nucleus were synthesized and their structures were evaluated. The antiproliferative activity of synthesized compounds against some cancer cells was investigated. The results have demonstrated that some dehydroepiandrosterone-17-hydrazone derivatives show distinct antiproliferative activity against some cancer cells through inducing cancer cell apoptosis, and compound 8 with a quinoline structure in 17-side chain displays excellent antiproliferative activity in vitro against SGC 7901 cancer cell (human gastric carcinoma) with an IC50 value of 1 μM. In addition, estrone-17-hydrazone derivatives having a key feature of indole group in the structure showed a special obvious cytotoxicity against HeLa cells, but almost inactive against other cells. The information obtained from the studies is valuable for the design of novel steroidal chemotherapeutic drugs. PMID:25578734
Photoinduced changes of surface order in coumarin side-chain polymer films used for liquid crystal photoalignment
Bergmann, G.; Jackson, P.O.; Hogg, J.H.C.; Stirner, T.; O'Neill, M.; Duffy, W.L.; Kelly, S.M.; Clark, G.F.
Specular x-ray reflectivity probes morphological changes in a crosslinkable coumarin photoalignment polymer film resulting from ultraviolet irradiation. An ordered surface layer with density oscillations compatible with planar side-chain alignment is obtained before irradiation. The ordering is enhanced in the early stages of crosslinking. This is attributed to the photoinduced increase of mobility of the side-chains resulting from the creation of free volume by the crosslinking process. The expansion of the thin film confirms that free volume is created. The surface ordering decreases with prolonged ultraviolet irradiation because of increased material viscosity resulting from a high crosslinked density. The implications of surface ordering on liquid crystal photoalignment are discussed.
Phenylalanyl-Glycyl-Phenylalanine Tripeptide: A Model System for Aromatic-Aromatic Side Chain Interactions in Proteins
Valdes, Haydee; Pluhackova, Kristyna; Hobza, Pavel
The performance of a wide range of quantum chemical calculations for the ab initio study of realistic model systems of aromatic-aromatic side chain interactions in proteins (in particular those π-π interactions occurring between adjacent residues along the protein sequence) is here assessed on the phenylalanyl-glycyl-phenylalanine (FGF) tripeptide. Energies and geometries obtained at different levels of theory are compared with CCSD(T)/CBS benchmark energies and RI-MP2/cc-pVTZ benchmark geometries, respectively. Consequently, a protocol of calculation alternative to the very expensive CCSD(T)/CBS is proposed. In addition to this, the preferred orientation of the Phe aromatic side chains is discussed and compared with previous results on the topic.
Control of the anchoring behavior of polymer-dispersed liquid crystals: effect of branching in the side chains of polyacrylates.
Zhou, Jian; Collard, David M; Park, Jung O; Srinivasarao, Mohan
A temperature-driven anchoring transition in a polymer/nematic fluid composite that is far from the bulk nematic-isotropic transition temperature is reported. A series of poly(methylheptyl acrylates) were studied to probe the subtle effects of the side chain structure of the polymer on control of the anchoring. A polymer-dispersed liquid crystal film made from TL205 and 1-methylheptyl acrylate shows only planar anchoring over the temperature range studied, while the films made from TL205 and each of the other methylheptyl acrylates or n-heptyl acrylate show the homeotropic-to-planar anchoring transition at temperatures between 70 and 78 degrees C. An interfacial model is proposed in which the different conformation of the side chains is suggested as the cause for the dramatic difference in the observed anchoring behavior. PMID:12188649
Calculation of electron paramagnetic resonance spectra from Brownian dynamics trajectories: application to nitroxide side chains in proteins.
Steinhoff, H J; Hubbell, W L
We present a method to simulate electron paramagnetic resonance spectra of spin-labeled proteins that explicitly includes the protein structure in the vicinity of the attached spin label. The method is applied to a spin-labeled polyleucine alpha-helix trimer. From short (6 ns) stochastic dynamics simulations of this trimer, an effective potential energy function is calculated. Interaction with secondary and tertiary structures determine the reorientational motion of the spin label side chains. After reduction to a single particle problem, long stochastic dynamic trajectories (700 ns) of the spin label side-chain reorientation are calculated from which the Lamor frequency trajectory and subsequently the electron paramagnetic resonance spectrum is determined. The simulated spectra agree well with experimental electron paramagnetic resonance spectra of bacteriorhodopsin mutants with spin labels in similar secondary and tertiary environments as in the polyleucine. Images FIGURE 1 PMID:8889196
A simple strategy to the side chain functionalization on the quinoxaline unit for efficient polymer solar cells.
Yuan, Jun; Qiu, Lixia; Zhang, Zhiguo; Li, Yongfang; He, Yuehui; Jiang, Lihui; Zou, Yingping
A new tetrafluoridequinoxaline electron accepting block from a quinoxaline core, which is substituted with a fluorine atom onto its backbone and side chains, was designed. A new copolymer (PBDTT-ffQx) was synthesized from tetrafluoridequinoxaline and benzodithiophene. The copolymer was characterized in detail. The photovoltaic properties were well investigated. A high PCE of 8.6% based on the single junction device was obtained. PMID:27025274
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB.
Maier, James A; Martinez, Carmenza; Kasavajhala, Koushik; Wickstrom, Lauren; Hauser, Kevin E; Simmerling, Carlos
Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reproduction of NMR χ1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements. PMID:26574453
Insight from molecular modelling: does the polymer side chain length matter for transport properties of perfluorosulfonic acid membranes?
Devanathan, Ramaswami; Dupuis, Michel
We present a detailed analysis of the nanostructure of short side chain (SSC) perfluorosulfonic acid membrane and its effect on H{sub 2}O network percolation, H{sub 3}O{sup +} and H{sub 2}O diffusion, and mean residence times of H{sub 3}O{sup +} and H{sub 2}O near SO{sub 3}{sup -} groups based on molecular dynamics simulations. We studied a range of hydration levels ({lambda}) at temperatures of 300 and 360 K, and compare the results to our previous findings in the benchmark Nafion membrane at 300 K. The water channel diameter is about 20% larger in Nafion, while the extent of SO3- clustering is more in SSC membrane. The calculated channel diameter is in excellent agreement with the recently proposed cylindrical water channel model of these membranes. The H{sub 2}O network percolation occurs at comparable hydration levels, and the diffusion coefficients of H{sub 2}O and H{sub 3}O{sup +} are similar in SSC and Nafion membranes. Raising the temperature of the SSC membrane from 300 to 360 K provides a much bigger increase in proton vehicular diffusion coefficient (by a factor of about 4) than changing the side chain length. H3O+ ions are found to exchange more frequently with SO{sub 3}{sup -} partners at the higher temperature. Our key findings are that (a) the hydrophobic-hydrophilic separation in the two membranes is surprisingly similar; (b) at all hydration levels studied, the longer side chain of Nafion is bent and is effectively equivalent to a short side chain in terms of extension into the water domain; and (c) proton transport along the centre of the channel is improbable and vehicular proton transport occurs between SO{sub 3}{sup -} groups. The simulations are validated by good agreement with corresponding experimental values for the simulated membrane density and diffusion coefficients of H{sub 2}O.
Independent Metrics for Protein Backbone and Side-Chain Flexibility: Time Scales and Effects of Ligand Binding.
Fuchs, Julian E; Waldner, Birgit J; Huber, Roland G; von Grafenstein, Susanne; Kramer, Christian; Liedl, Klaus R
Conformational dynamics are central for understanding biomolecular structure and function, since biological macromolecules are inherently flexible at room temperature and in solution. Computational methods are nowadays capable of providing valuable information on the conformational ensembles of biomolecules. However, analysis tools and intuitive metrics that capture dynamic information from in silico generated structural ensembles are limited. In standard work-flows, flexibility in a conformational ensemble is represented through residue-wise root-mean-square fluctuations or B-factors following a global alignment. Consequently, these approaches relying on global alignments discard valuable information on local dynamics. Results inherently depend on global flexibility, residue size, and connectivity. In this study we present a novel approach for capturing positional fluctuations based on multiple local alignments instead of one single global alignment. The method captures local dynamics within a structural ensemble independent of residue type by splitting individual local and global degrees of freedom of protein backbone and side-chains. Dependence on residue type and size in the side-chains is removed via normalization with the B-factors of the isolated residue. As a test case, we demonstrate its application to a molecular dynamics simulation of bovine pancreatic trypsin inhibitor (BPTI) on the millisecond time scale. This allows for illustrating different time scales of backbone and side-chain flexibility. Additionally, we demonstrate the effects of ligand binding on side-chain flexibility of three serine proteases. We expect our new methodology for quantifying local flexibility to be helpful in unraveling local changes in biomolecular dynamics. PMID:26579739
Study of Class I and Class III Polyhydroxyalkanoate (PHA) Synthases with Substrates Containing a Modified Side Chain.
Jia, Kaimin; Cao, Ruikai; Hua, Duy H; Li, Ping
Polyhydroxyalkanoates (PHAs) are carbon and energy storage polymers produced by a variety of microbial organisms under nutrient-limited conditions. They have been considered as an environmentally friendly alternative to oil-based plastics due to their renewability, versatility, and biodegradability. PHA synthase (PhaC) plays a central role in PHA biosynthesis, in which its activity and substrate specificity are major factors in determining the productivity and properties of the produced polymers. However, the effects of modifying the substrate side chain are not well understood because of the difficulty to accessing the desired analogues. In this report, a series of 3-(R)-hydroxyacyl coenzyme A (HACoA) analogues were synthesized and tested with class I synthases from Chromobacterium sp. USM2 (PhaCCs and A479S-PhaCCs) and Caulobacter crescentus (PhaCCc) as well as class III synthase from Allochromatium vinosum (PhaECAv). It was found that, while different PHA synthases displayed distinct preference with regard to the length of the alkyl side chains, they could withstand moderate side chain modifications such as terminal unsaturated bonds and the azide group. Specifically, the specific activity of PhaCCs toward propynyl analogue (HHxyCoA) was only 5-fold less than that toward the classical substrate HBCoA. The catalytic efficiency (kcat/Km) of PhaECAv toward azide analogue (HABCoA) was determined to be 2.86 × 10(5) M(-1) s(-1), which was 6.2% of the value of HBCoA (4.62 × 10(6) M(-1) s(-1)) measured in the presence of bovine serum albumin (BSA). These side chain modifications may be employed to introduce new material functions to PHAs as well as to study PHA biogenesis via click-chemistry, in which the latter remains unknown and is important for metabolic engineering to produce PHAs economically. PMID:26974339
Palladium-Assisted Removal of a Solubilizing Tag from a Cys Side Chain To Facilitate Peptide and Protein Synthesis.
Maity, Suman Kumar; Mann, Guy; Jbara, Muhammad; Laps, Shay; Kamnesky, Guy; Brik, Ashraf
Reversible attachment of solubilizing tags to hydrophobic peptides to facilitate their purification and ligation is an essential yet challenging task in chemical protein synthesis. The efficient palladium-assisted removal of the solubilizing tag linked to the Cys side chain is reported. The strategy was applied for the efficient preparation of histone protein H4 from two fragments via one-pot operation of ligation, removal of the solubilizing tag, and desulfurization. PMID:27268382
Backrub-like backbone simulation recapitulates natural protein conformational variability and improves mutant side-chain prediction
Smith, Colin A.; Kortemme, Tanja
Summary Incorporation of effective backbone sampling into protein simulation and design is an important step in increasing the accuracy of computational protein modeling. Recent analysis of high-resolution crystal structures has suggested a new model, termed backrub, to describe localized, hinge-like alternative backbone and side chain conformations observed in the crystal lattice. The model involves internal backbone rotations about axes between Cα atoms. Based on this observation, we have implemented a backrub-inspired sampling method in the Rosetta structure prediction and design program. We evaluate this model of backbone flexibility using three different tests. First, we show that Rosetta backrub simulations recapitulate the correlation between backbone and side-chain conformations in the high-resolution crystal structures upon which the model was based. As a second test of backrub sampling, we show that backbone flexibility improves the accuracy of predicting point-mutant side chain conformations over fixed backbone rotameric sampling alone. Finally, we show that backrub sampling of triosephosphate isomerase loop 6 can capture the ms/µs oscillation between the open and closed states observed in solution. Our results suggest that backrub sampling captures a sizable fraction of localized conformational changes that occur in natural proteins. Application of this simple model of backbone motions may significantly improve both protein design and atomistic simulations of localized protein flexibility. PMID:18547585
Two Novel Norwithasteroids with Unusual Six- and Seven-Membered Ether Rings in Side Chain from Flos Daturae
Yang, Bing-You; Xia, Yong-Gang; Wang, Yan-Yan; Wang, Qiu-Hong; Kuang, Hai-Xue
Chemical investigation of 50% ethanol eluate fraction of macroporous resin for the flower of Datura metel L. collected in Jiangsu province of China resulted in the isolation of two novel naturally occurring norwithasteroids, baimantuoluoline I (1) and baimantuoluoside J (2). Their structures were elucidated as 5α, 6β, 12β-trihydroxy-1-oxo-2-en-ergosta-21,24;22,29-diepoxy-26-carboxylic acid (1) and 5α, 6β, 12β, 25-tetrahydroxy-1-oxo-2-en-ergosta-21,24;22,29-diepoxy-26-carboxylic acid (2) on the basis of extensive spectroscopic analysis, including 1D, 2D-NMR, and HR-ESI-MS. According to the literatures, this study represents the first report of the norwithasteroids in the side chain with unusual six- and seven-membered ether rings instead of those with an unmodified skeleton (δ-lactone or δ-lactol side chain) and a modified skeleton (γ-lactone or γ-lactol side chain) in the family of withanolides. Meanwhile, compounds 1 and 2 were evaluated for their immunosuppressive activity against mice splenocyte proliferation in vitro. PMID:23606878
δ-Methyl Branching in the Side Chain Makes the Difference: Access to Room-Temperature Discotics.
Kirres, Jochen; Knecht, Friederike; Seubert, Philipp; Baro, Angelika; Laschat, Sabine
Although discotic liquid crystals are attractive functional materials, their use in electronic devices is often restricted by high melting and clearing points. Among the promising candidates for applications are [15]crown-5 ether-based liquid crystals with peripheral n-alkoxy side chains, which, however, still have melting points above room temperature. To overcome this problem, a series of o-terphenyl and triphenylene [15]crown-5 ether derivatives was prepared in which δ-methyl-branched alkoxy side chains of varying lengths substitute the peripheral linear alkoxy chains. The mesomorphic properties of the novel crown ethers were studied by differential scanning calorimetry, polarizing optical microscopy, and X-ray diffraction. δ-Methyl branching indeed lowers melting points resulting in room-temperature hexagonal columnar mesophases. The mesophase widths, which ranged from 87 to 30 K for o-terphenyls, significantly increased to 106-147 K for the triphenylenes depending on the chain lengths, revealing the beneficial effect of a flat mesogen, due to improved π-π interactions. PMID:26853226
Influence of the side chain and substrate on polythiophene thin film surface, bulk, and buried interfacial structures.
Xiao, Minyu; Jasensky, Joshua; Zhang, Xiaoxian; Li, Yaoxin; Pichan, Cayla; Lu, Xiaolin; Chen, Zhan
The molecular structures of organic semiconducting thin films mediate the performance of various devices composed of such materials. To fully understand how the structures of organic semiconductors alter on substrates due to different polymer side chains and different interfacial interactions, thin films of two kinds of polythiophene derivatives with different side-chains, poly(3-hexylthiophene) (P3HT) and poly(3-potassium-6-hexanoate thiophene) (P3KHT), were deposited and compared on various surfaces. A combination of analytical tools was applied in this research: contact angle goniometry and X-ray photoelectron spectroscopy (XPS) were used to characterize substrate dielectric surfaces with varied hydrophobicity for polymer film deposition; X-ray diffraction and UV-vis spectroscopy were used to examine the polythiophene film bulk structure; sum frequency generation (SFG) vibrational spectroscopy was utilized to probe the molecular structures of polymer film surfaces in air and buried solid/solid interfaces. Both side-chain hydrophobicity and substrate hydrophobicity were found to mediate the crystallinity of the polythiophene film, as well as the orientation of the thiophene ring within the polymer backbone at the buried polymer/substrate interface and the polymer thin film surface in air. For the same type of polythiophene film deposited on different substrates, a more hydrophobic substrate surface induced thiophene ring alignment with the surface normal at both the buried interface and on the surface in air. For different films (P3HT vs. P3KHT) deposited on the same dielectric substrate, a more hydrophobic polythiophene side chain caused the thiophene ring to align more towards the surface at the buried polymer/substrate interface and on the surface in air. We believe that the polythiophene surface, bulk, and buried interfacial molecular structures all influence the hole mobility within the polythiophene film. Successful characterization of an organic conducting
Utilizing alkoxyphenyl substituents for side-chain engineering of efficient benzo[1,2-b:4,5-b']dithiophene-based small molecule organic solar cells.
Du, Zhengkun; Chen, Weichao; Qiu, Meng; Chen, Yanhua; Wang, Ning; Wang, Ting; Sun, Mingliang; Yu, Donghong; Yang, Renqiang
A new two-dimensional (2D) conjugated small molecule, namely DCA3TBDTP, with an alkoxyphenyl substituted benzo[1,2-b:4,5-b']dithiophene (BDT) unit as the central core, octyl cyanoacetate as the end-capped groups and terthiophene as the π-linked bridge, was designed and synthesized for solution-processed organic solar cells (OSCs) as an electron donor material, in which an alkoxyphenyl group was introduced as a weak electron-donating side chain of the BDT moiety. The DCA3TBDTP molecule exhibited good solubility, a deep highest occupied molecular orbital (HOMO) level (-5.25 eV), an appropriate optical band-gap (1.82 eV) and a high decomposition temperature (362 °C). By applying the simple solution spin-coating fabrication process, the bulk heterojunction (BHJ) OSCs based on DCA3TBDTP and [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) exhibited a good power conversion efficiency (PCE) of 4.51% with a high open-circuit voltage (Voc) of 0.90 V when thermal annealing at only 70 °C. PMID:26077329
A novel assay for typing Rh antigens in blood-stains using a lectin specific to the bisecting N-acetyl-D-glucosamine side chain of glycoprotein.
Matsubara, K; Tanabe, K; Akane, A; Nakamura, H; Takahashi, S; Kimura, K
A unique sandwich enzyme-linked immunosorbent assay for the determination of Rh antigens in blood stains has been developed using Rh antisera and phaseolus vulgaris E4/peroxidase conjugate (PHAE4/PO). The appropriate antiserum for detecting Rh C, c, D, E or e was coated on the inner surface of microplate wells, and the sample antigens from blood stains, solubilized with n-octyl-beta-D-glucopyranoside, were then placed in the wells. After washing the wells repeatedly, PHAE4/PO was added. Bound PHAE4/PO was detected by the development of colors using o-phenylenediamine/H2O2. All Rh antigens corresponding to the antisera were clearly detected using this technique. The detection limit expressed by sample dilution was more than 2 x 10(5) times (volume/dried blood weight) for the various antigens from the fresh 5 x 5 mm2 blood stain. Even when the blood stain samples were left beside a sunny window at room temperature for 2 months, Rh antigens were still detected. When the ABH, MN, P1, Kidd, Duffy and Lewis blood grouping systems were tested with similar ELISA procedures PHAE4 did not recognize any antigen. Since PHAE4 specifically recognizes and combines with the bisecting N-acetyl-D-glucosamine side chain, it was concluded that the glycoprotein was a component of all Rh antigens immune complexes. PMID:8046252
Gel-like elasticity in glass-forming side-chain liquid-crystal polymers
NASA Astrophysics Data System (ADS)
Pozo, O.; Collin, D.; Finkelmann, H.; Rogez, D.; Martinoty, P.
We study the complex shear modulus G of two side-chain liquid-crystal polymers (SCLCPs), a methoxy-phenylbenzoate substituted polyacrylate (thereafter called PAOCH3 ), and a cyanobiphenyl substituted polyacrylate supplied by Merck (thereafter called LCP105) using a piezoelectric rheometer. Two methods of filling the cell are used: (a) a capillary method, which can be used only at high temperature because of the low value of the viscosity, and (b) the classical one, thereafter called compression method, which consists in placing the sample between the two slides of the cell and to bring them closer. By filling the cell at high temperature either with the compression or the capillary method, we show that the response of both compounds is liquidlike ( G'˜f2 and G″˜f , where f is the frequency) for temperatures higher than a certain temperature T0 and gel-like (G'˜const,G″˜f) below T0 . This change in behavior from the conventional flow response to a gel-like response, when approaching the glass transition, is observed for nonsliding conditions and for very weak-imposed shear strains. It can be explained by a percolation-type mechanism of preglassy elastic clusters, which correspond to long-range and long-lived density fluctuations that are frozen at the time scale of the experiment. The sample response is therefore the sum of two contributions: one is due to the flow response of the polymer melt and the other to the elastic response of the network formed by the preglassy elastic clusters. By filling the cell below T0 with the compression method, both compounds exhibit a gel-type behavior by gently bringing closer the slides of the cell and an anomalous low-frequency behavior characterized by G'=const and G″=const by increasing the pressure used to bring closer the slides of the cell. A compression-assisted aggregation of the preglassy elastic clusters can explain both the increase in the low-frequency elastic plateau when the sample thickness is decreased
One- and two-photon excitations of σ-conjugated chains
NASA Astrophysics Data System (ADS)
Soos, Z. G.; Hayden, G. W.
The Sandorfy C model of alternating transfer integrals t(1 ± δ) for σ conjugation in (SiRR') n polymers is extended to include Coulomb interactions. The resulting Pariser-Parr-Pople (PPP) models are solved exactly for oligomers with n⩽6 and extrapolated to polymers. Increasing alternation δ reverses the position of the one-photon excitation to 1 1B and two-photon excitation to 2 1A for PPP parameters appropriate to either polyenes with δ⩽0.10 or polysilanes (PS) with δ ≈ 1/3. The PS excitation to 1 1B is about 1 eV below the 2 1A level due to exciton formation. The corresponding states are essentially degenerate in Hubbard models restricted to on-site interactions U=2 t for δ>0.10. The dimer limit (δ ≈ 1) relates PPP or Hubbard models and their microscopic parameters to bond, charge-transfer, and triplet excitons and rationalizes the numerical results for arbitrary δ.
All-acrylic multigraft copolymers: Effect of side chain molecular weight and volume fraction on mechanical behavior
Goodwin, Andrew; Wang, Weiyu; Kang, Nam -Goo; Wang, Yangyang; Hong, Kunlun; Mays, Jimmy
We present in this paper the synthesis of poly(n-butyl acrylate)-g-poly(methyl methacrylate) (PnBA-g-PMMA) multigraft copolymers via a grafting-through (macromonomer) approach. The synthesis was performed using two controlled polymerization techniques. The PMMA macromonomer was obtained by high-vacuum anionic polymerization followed by the copolymerization of n-butyl acrylate and PMMA macromonomer using reversible addition–fragmentation chain transfer (RAFT) polymerization to yield the desired all-acrylic multigraft structures. The PnBA-g-PMMA multigraft structures exhibit randomly spaced branch points with various PMMA contents, ranging from 15 to 40 vol %, allowing an investigation into how physical properties vary with differences in the number of branch points and molecular weightmore » of grafted side chains. The determination of molecular weight and polydispersity indices of both the PMMA macromonomer and the graft copolymers was carried out using size exclusion chromatography with triple detection, and the structural characteristics of both the macromonomer and PnBA-g-PMMA graft materials were characterized by 1H and 13C NMR. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was employed for monitoring the macromonomer synthesis. Thermal characteristics of the materials were analyzed using differential scanning calorimetry and thermogravimetric analysis. The mechanical performance of the graft materials was characterized by rheology and dynamic mechanical analysis, revealing that samples with PMMA content of 25–40 vol % exhibit superior elastomeric properties as compared to materials containing short PMMA side chains or <25 vol % PMMA. In conclusion, atomic force microscopy showed a varying degree of microphase separation between the glassy and rubbery components that is strongly dependent on PMMA side chain molecular weight.« less
All-acrylic multigraft copolymers: Effect of side chain molecular weight and volume fraction on mechanical behavior
Goodwin, Andrew; Wang, Weiyu; Kang, Nam -Goo; Wang, Yangyang; Hong, Kunlun; Mays, Jimmy
We present in this paper the synthesis of poly(n-butyl acrylate)-g-poly(methyl methacrylate) (PnBA-g-PMMA) multigraft copolymers via a grafting-through (macromonomer) approach. The synthesis was performed using two controlled polymerization techniques. The PMMA macromonomer was obtained by high-vacuum anionic polymerization followed by the copolymerization of n-butyl acrylate and PMMA macromonomer using reversible addition–fragmentation chain transfer (RAFT) polymerization to yield the desired all-acrylic multigraft structures. The PnBA-g-PMMA multigraft structures exhibit randomly spaced branch points with various PMMA contents, ranging from 15 to 40 vol %, allowing an investigation into how physical properties vary with differences in the number of branch points and molecular weight of grafted side chains. The determination of molecular weight and polydispersity indices of both the PMMA macromonomer and the graft copolymers was carried out using size exclusion chromatography with triple detection, and the structural characteristics of both the macromonomer and PnBA-g-PMMA graft materials were characterized by 1H and 13C NMR. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was employed for monitoring the macromonomer synthesis. Thermal characteristics of the materials were analyzed using differential scanning calorimetry and thermogravimetric analysis. The mechanical performance of the graft materials was characterized by rheology and dynamic mechanical analysis, revealing that samples with PMMA content of 25–40 vol % exhibit superior elastomeric properties as compared to materials containing short PMMA side chains or <25 vol % PMMA. In conclusion, atomic force microscopy showed a varying degree of microphase separation between the glassy and rubbery components that is strongly dependent on PMMA side chain molecular weight.
Helix-Coil Transition and Association Behavior of Water-Soluble Polypeptides Having Hydrophobic Alkyl Side Chains
NASA Astrophysics Data System (ADS)
Inomata, Katsuhiro; Takai, Tomokazu; Ohno, Noriyoshi; Yamaji, Yoshiaki; Yamada, Erina; Sugimoto, Hideki; Nakanishi, Eiji
Water soluble polypeptide, poly[N 5-(2-hydroxyethyl) L-glutamine] (PHEG), was hydrophobiocally modified partially along the main chain by long alkyl groups -(CH2) n-1CH3 (Cn) as side chains. Association and viscoelastic behavior of solutions of these self-assembling polymers (PHEG-g-Cn, n = 12, 16 and 18) were investigated by means of steady-flow viscosity and linear dynamic viscoelasticity measurements. In the mixed solvent of water/ethylene glycol (EG), the main chain of PHEG-g-Cn changed its conformation from flexible random coil to rodlike α-helix with the increase in EG content of the solvent. When the solvent was pure water, existence of the associative alkyl chains induced a drastic increase in shear flow viscosity (η) than PHEG homopolymer, probably because of formation of self-assembled large aggregates via intermolecular association. When EG was used as solvent, η and the elastic storage modulus (G') of the solution revealed a unique concentration dependence, i.e., η and G' of PHEG-g-C18 solution at 20 wt% were smaller than those at 15 wt%. These viscoelastic behaviors may be described by the α-helical rodlike conformation of PHEG main chain, which is suitable to form an ordered anisotropic phase like lyotropic liquid crystal, with destruction of a physically crosslinked network structure.
Stabilization of Charge Carriers in Picket-Fence Polythiophenes Using Dielectric Side Chains.
Zhao, Chunhui; Sakurai, Tsuneaki; Yoneda, Satoru; Seki, Shu; Sugimoto, Manabu; Oki, Choji; Takeuchi, Masayuki; Sugiyasu, Kazunori
Insulated molecular wires (IMWs) are π-conjugated polymers that are molecularly sheathed with an insulating layer and are structurally analogous to electric power cords at the nanoscale. Such unique architectures are expected in molecular electronics and organic devices. Herein, we propose a new molecular design concept of IMWs, in which the sheaths can be customized, thereby enabling the modulation of the electronic properties of the interior π-conjugated systems. To this end, we focused our attention on the dielectric constant of the sheaths, as it governs the electrostatic interaction between charges. Upon doping, charge carriers, such as polaron and bipolaron, were generated regardless of the dielectric properties of the sheaths. Flash-photolysis time-resolved microwave conductivity measurements revealed that intrawire charge carrier mobility was independent of the sheaths. However, we found that the charge carriers could be stabilized by the sheaths with a high dielectric constant owing to the charge screening effect. We expect that IMWs designed in this way will be useful in a variety of applications, where the nature of charge carriers plays an important role, and particularly when redox switching is required (e.g., electrochromic, magnetic, and memory applications). PMID:27503254
Monoclonal antibody binding to peptide epitopes conjugated to synthetic branched chain polypeptide carriers. Influence of the carrier upon antibody recognition.
Hudecz, F; Price, M R
The peptide C A P D T R P A P G has been linked covalently to defined branched polypeptides with a polylysine backbone and side chains of DL-alanine or D-leucine-DL-alanine oligopeptides. The peptide was coupled via its N terminal cysteine to the side chains of the macromolecular carrier to ensure uniform orientation. The compounds were subjected to compositional analyses to characterise the degrees of substitution and secondary structural studies were performed using circular dichroism spectroscopy. The peptide selected for investigation contains the immunodominant sequence P D T R P A P which is expressed in the protein core of epithelial mucins. It is to this region that many anti-mucin monoclonal antibodies bind (Burchell et al., 1989; Price et al., 1990a,b). With these characterised constructs, it has been possible to evaluate the influence of secondary structure upon the binding of monoclonal antibodies which recognise short linear sequences in the synthetic antigenic peptide. The findings are relevant to the design and construction of synthetic immunogens and vaccines as well as to the production of synthetic analogues of clinically relevant antigens (in this case, epithelial mucins associated with breast and ovarian carcinomas). PMID:1372334
Immunochemical characterization of synthetic hexa-, octa- and decasaccharide conjugate vaccines for Vibrio cholerae O:1 Serotype Ogawa with emphasis on antigenic density and chain length
Ftacek, Peter; Nelson, Victor; Szu, Shousun C.
Cholera remains to be a global health problem without suitable vaccines for endemic control or outbreak relief. Here we describe a new parenteral vaccine based on neoglyco-conjugate of synthetic fragments of O-specific polysaccharide (O-SP) of Vibrio cholerae O1, serotype Ogawa. Hexa-, octa- and decasaccharides of the O-SP with carboxylic acid at the reducing end were chemically synthesized and conjugated to tetanus toxoid (TT). The conjugates prepared by a novel linking scheme consisted of 17-atom linker of hydrazide and alkyl bonds elicited robust serum IgG anti-LPS responses with vibriocidal activities in mice. There is a length dependence in immune response with decasaccharide conjugates elicited the highest anti-LPS IgG. There seems to be an indication that regardless of the carbohydrate chain length, a molar ratio of 230±10 monosaccharide units per TT induced high antibody response. The conjugates also elicited cross-reactive antibodies to serotype Inaba. The formulation of the proposed cholera conjugate vaccine, similar to other licensed polysaccharide vaccine, is suitable for children immunization. A parenteral cholera vaccine could overcome the diminishing immunogenicity in most of oral vaccines due to the gastrointestinal complexity and environmental enteropathy in children living in impoverished environment and could be considered for global cholera immunization. PMID:23955520
Immunochemical characterization of synthetic hexa-, octa- and decasaccharide conjugate vaccines for Vibrio cholerae O:1 serotype Ogawa with emphasis on antigenic density and chain length.
Ftacek, Peter; Nelson, Victor; Szu, Shousun C
Cholera remains to be a global health problem without suitable vaccines for endemic control or outbreak relief. Here we describe a new parenteral vaccine based on neoglyco-conjugate of synthetic fragments of O-specific polysaccharide (O-SP) of Vibrio cholerae O1, serotype Ogawa. Hexa-, octa- and decasaccharides of the O-SP with carboxylic acid at the reducing end were chemically synthesized and conjugated to tetanus toxoid (TT). The conjugates prepared by a novel linking scheme consisted of 17-atom linker of hydrazide and alkyl bonds elicited robust serum IgG anti-LPS responses with vibriocidal activities in mice. There is a length dependence in immune response with decasaccharide conjugates elicited the highest anti-LPS IgG. There seems to be an indication that regardless of the carbohydrate chain length, a molar ratio of 230 ± 10 monosaccharide units per TT induced high antibody response. The conjugates also elicited cross-reactive antibodies to serotype Inaba. The formulation of the proposed cholera conjugate vaccine, similar to other licensed polysaccharide vaccine, is suitable for children immunization. A parenteral cholera vaccine could overcome the diminishing immunogenicity in most of oral vaccines due to the gastrointestinal complexity and environmental enteropathy in children living in impoverished environment and could be considered for global cholera immunization. PMID:23955520
Polypropylene non-woven meshes with conformal glycosylated layer for lectin affinity adsorption: the effect of side chain length.
Ye, Xiang-Yu; Huang, Xiao-Jun; Xu, Zhi-Kang
The unique characteristics of polypropylene non-woven meshes (PPNWMs), like random network of overlapped fibers, multiple connected pores and overall high porosity, make them high potentials for use as separation or adsorption media. Meanwhile, carbohydrates can specifically recognize certain lectin through multivalent interactions. Therefore glycosylated PPNWMs, combing the merits of both, can be regarded as superior affinity membranes for lectin adsorption and purification. Here, we describe a versatile strategy for the glycosylation of PPNWMs. Two hydrophilic polymers with different side chain length, poly(2-hydroxyethyl methacrylate) (PHEMA) and poly(oligo(ethylene glycol) methacrylate) (POEGMA), were first conformally tethered on the polypropylene fiber surface by a modified plasma pretreatment and benzophenone (BP) entrapment UV irradiation process. Then glucose ligands were bound through the reaction between the hydroxyl group and acetyl glucose. Chemical changes of the PPNWMs surface were monitored by FT-IR/ATR. SEM pictures show that conformal glucose ligands can be achieved through the modified process. After deprotection, the glycosylated PPNWMs became superhydrophilic and had high specific recognition capability toward Concanavalin A (Con A). Static Con A adsorption experiments were further performed and the results indicate that fast adsorption kinetics and high binding capacity can be accomplished at the same time. We also found that increasing the side chain length of polymer brushes had positive effect on protein binding capacity due to improved chain mobility. Model studies suggest a multilayer adsorption behavior of Con A. PMID:24398082
Amino acid side chain-like surface modification on magnetic nanoparticles for highly efficient separation of mixed proteins.
Lee, Soo Youn; Ahn, Chi Young; Lee, Jiho; Chang, Jeong Ho
This work reports on the realization of specific functionalized silica-coated magnetic nanoparticles (Si-MNPs) for effective protein separation through surface modification with various amino acid side chain-like functional groups such as thiol (-SH), disulfide (-S-S-), carbon chain (-C(n)), carboxyl (-COOH), amine (-NH(2)), and aldehyde (-CHO). This study also suggests an improved and convenient method for the synthesis of functionalized Si-MNPs by hydrolysis condensation with silan-coupling agents. The protein adsorption effects in a coexistent mixed state are explored using various proteins, which have different isoelectric point (pI) values and molecular weights, in order to elucidate the binding performance of different proteins one solution. The adsorption efficiency of bovine serum albumin (BSA; 66 kDa; pI=4.65) and lysozyme (LYZ; 14.3 kDa; pI=11) is 70-100% with various amino acid side chain-like functional groups. However, the adsorption efficiency of a mixed protein solution of BSA and LYZ was different. Although the relatively bulky BSA molecule displayed 50% and 20% adsorption corresponding to pH 4.65, and pH 11, respectively, the smaller LYZ provided almost 100% adsorption at both pH 4.65 and pH 11. PMID:22483893
Solid-Phase Synthesis with Attachment of Peptide to Resin through an Amino Acid Side Chain: [8-Lysine]-Vasopressin
Meienhofer, Johannes; Trzeciak, Arnold
It is proposed that the scope of solid-phase peptide synthesis could be considerably broadened by attaching peptides to the solid-phase through functional side-chain groups rather than through the commonly used α-carboxyl groups. Side-chain attachment offers the use of a large variety of chemical linkages to solid supports. Attachment through the ε-amino group of the lysine residue to a polystyrene resin has been applied to a solid-phase synthesis of lysine-vasopressin. Nα-tert-butyl-oxycarbonyl-L-lysyl-glycinamide was condensed with chloroformoxymethyl polystyrene-2% divinylbenzene resin. After removal of the Nα-protecting tert-butyloxycarbonyl group, the peptide chain was elongated by standard Merrifield procedures to give Tos-Cys(Bzl)-Tyr-Phe-Glu-(NH2) - Asp(NH2) - Cys(Bzl) - Pro - Lys(Z - resin) - Gly-NH2. Cleavage from the resin with HBr in dioxane or trifluoroacetic acid gave a partially protected nonapeptide hydrobromide. For purification, it was converted into a fully protected peptide by treatment with benzyl p-nitro-phenyl carbonate and crystallized. Deprotection by sodium in liquid ammonia, oxidative cyclization, IRC-50 desalting, and ion-exchange chromatography gave lysinevasopressin with high potency in a rat-pressor assay. PMID:5280519
On the ability of molecular dynamics force fields to recapitulate NMR derived protein side chain order parameters.
O'Brien, Evan S; Wand, A Joshua; Sharp, Kim A
Molecular dynamics (MD) simulations have become a central tool for investigating various biophysical questions with atomistic detail. While many different proxies are used to qualify MD force fields, most are based on largely structural parameters such as the root mean square deviation from experimental coordinates or nuclear magnetic resonance (NMR) chemical shifts and residual dipolar couplings. NMR derived Lipari-Szabo squared generalized order parameter (O(2) ) values of amide NH bond vectors of the polypeptide chain were also often employed for refinement and validation. However, with a few exceptions, side chain methyl symmetry axis order parameters have not been incorporated into experimental reference sets. Using a test set of five diverse proteins, the performance of several force fields implemented in the NAMDD simulation package was examined. It was found that simulations employing explicit water implemented using the TIP3 model generally performed significantly better than those using implicit water in reproducing experimental methyl symmetry axis O(2) values. Overall the CHARMM27 force field performs nominally better than two implementations of the Amber force field. It appeared that recent quantum mechanics modifications to side chain torsional angles of leucine and isoleucine in the Amber force field have significantly hindered proper motional modeling for these residues. There remained significant room for improvement as even the best correlations of experimental and simulated methyl group Lipari-Szabo generalized order parameters fall below an R(2) of 0.8. PMID:26990788
Water-Soluble Poly(L-serine)s with Elongated and Charged Side-Chains: Synthesis, Conformations and Cell-Penetrating Properties
Tang, Haoyu; Yin, Lichen; Lu, Hua; Cheng, Jianjun
Water-soluble poly(L-serine)s bearing long side-chain with terminal charge groups were synthesized via ring-opening polymerization of O-pentenyl-L-serine N-carboxyanhydride followed by thiol-ene reactions. These side-chain modified poly(L-serine)s adopt β-sheet conformation in aqueous solution with excellent stability against changes in pH and temperature. These water-soluble poly(L-serine) derivatives with charged side-chain functional groups and stable β-sheet conformations showed membrane-penetrating capabilities in different cell lines with low cytotoxicity. PMID:22853191
Modification of eucalyptus pulp fiber using silane coupling agents with aliphatic side chains of different length
Technology Transfer Automated Retrieval System (TEKTRAN)
The objective of this work was to evaluate the effect of three silane coupling agents with different aliphatic chain lengths on the hydrophobicity of eucalyptus pulp fiber. The three silanes coupling agents used (isobutyltrimethoxysilane, methyltrimethoxysilane, and n-octyltriethoxysilane [OTES]) we...
Syntheses of protoporphyrin-IX derivatives bearing extended propionate side-chains.
Holmes, Robert T; Lu, Jianming; Mwakwari, Celinah; Smith, Kevin M
In order to investigate the relationship between depth within membranes of singlet oxygen generation and effectiveness of photodynamic therapy of tumors, analogs of protoporphyrin-IX 1 bearing five 4 and seven 5 carbon atoms (in place of the 3-carbon atom chain in 1) were synthesized from monopyrrole precursors. PMID:20161404
Protein loops, solitons, and side-chain visualization with applications to the left-handed helix region
NASA Astrophysics Data System (ADS)
Lundgren, Martin; Niemi, Antti J.; Sha, Fan
Folded proteins have a modular assembly. They are constructed from regular secondary structures like α helices and β strands that are joined together by loops. Here we develop a visualization technique that is adapted to describe this modular structure. In complement to the widely employed Ramachandran plot that is based on toroidal geometry, our approach utilizes the geometry of a two sphere. Unlike the more conventional approaches that describe only a given peptide unit, ours is capable of describing the entire backbone environment including the neighboring peptide units. It maps the positions of each atom to the surface of the two-sphere exactly how these atoms are seen by an observer who is located at the position of the central Cα atom. At each level of side-chain atoms we observe a strong correlation between the positioning of the atom and the underlying local secondary structure with very little if any variation between the different amino acids. As a concrete example we analyze the left-handed helix region of nonglycyl amino acids. This region corresponds to an isolated and highly localized residue independent sector in the direction of the Cβ carbons on the two-sphere. We show that the residue independent localization extends to Cγ and Cδ carbons and to side-chain oxygen and nitrogen atoms in the case of asparagine and aspartic acid. When we extend the analysis to the side-chain atoms of the neighboring residues, we observe that left-handed β turns display a regular and largely amino acid independent structure that can extend to seven consecutive residues. This collective pattern is due to the presence of a backbone soliton. We show how one can use our visualization techniques to analyze and classify the different solitons in terms of selection rules that we describe in detail.
Evaluating the Effect of Ionic Strength on Duplex Stability for PNA Having Negatively or Positively Charged Side Chains
De Costa, N. Tilani S.; Heemstra, Jennifer M.
The enhanced thermodynamic stability of PNA:DNA and PNA:RNA duplexes compared with DNA:DNA and DNA:RNA duplexes has been attributed in part to the lack of electrostatic repulsion between the uncharged PNA backbone and negatively charged DNA or RNA backbone. However, there are no previously reported studies that systematically evaluate the effect of ionic strength on duplex stability for PNA having a charged backbone. Here we investigate the role of charge repulsion in PNA binding by synthesizing PNA strands having negatively or positively charged side chains, then measuring their duplex stability with DNA or RNA at varying salt concentrations. At low salt concentrations, positively charged PNA binds more strongly to DNA and RNA than does negatively charged PNA. However, at medium to high salt concentrations, this trend is reversed, and negatively charged PNA shows higher affinity for DNA and RNA than does positively charged PNA. These results show that charge screening by counterions in solution enables negatively charged side chains to be incorporated into the PNA backbone without reducing duplex stability with DNA and RNA. This research provides new insight into the role of electrostatics in PNA binding, and demonstrates that introduction of negatively charged side chains is not significantly detrimental to PNA binding affinity at physiological ionic strength. The ability to incorporate negative charge without sacrificing binding affinity is anticipated to enable the development of PNA therapeutics that take advantage of both the inherent benefits of PNA and the multitude of charge-based delivery technologies currently being developed for DNA and RNA. PMID:23484047
Evaluating the effect of ionic strength on duplex stability for PNA having negatively or positively charged side chains.
De Costa, N Tilani S; Heemstra, Jennifer M
The enhanced thermodynamic stability of PNA:DNA and PNA:RNA duplexes compared with DNA:DNA and DNA:RNA duplexes has been attributed in part to the lack of electrostatic repulsion between the uncharged PNA backbone and negatively charged DNA or RNA backbone. However, there are no previously reported studies that systematically evaluate the effect of ionic strength on duplex stability for PNA having a charged backbone. Here we investigate the role of charge repulsion in PNA binding by synthesizing PNA strands having negatively or positively charged side chains, then measuring their duplex stability with DNA or RNA at varying salt concentrations. At low salt concentrations, positively charged PNA binds more strongly to DNA and RNA than does negatively charged PNA. However, at medium to high salt concentrations, this trend is reversed, and negatively charged PNA shows higher affinity for DNA and RNA than does positively charged PNA. These results show that charge screening by counterions in solution enables negatively charged side chains to be incorporated into the PNA backbone without reducing duplex stability with DNA and RNA. This research provides new insight into the role of electrostatics in PNA binding, and demonstrates that introduction of negatively charged side chains is not significantly detrimental to PNA binding affinity at physiological ionic strength. The ability to incorporate negative charge without sacrificing binding affinity is anticipated to enable the development of PNA therapeutics that take advantage of both the inherent benefits of PNA and the multitude of charge-based delivery technologies currently being developed for DNA and RNA. PMID:23484047
On the source of entropic elastomeric force in polypeptides and proteins: Backbone configurational vs. side-chain solvational entropy
Luan, Chihao; Jaggard, J.; Harris, R.D.; Urry, D.W. )
At physiological temperature in water, the relaxed state of the protein, elastin, and model elastomeric sequential polypeptides derived from this biological elastomer is the result of an inverse temperature transition. At lower temperatures, say at 20{degree}C, the hydrophobic side chains of the elastomers are hydrated with a low-entropy net of water. Following Flory and colleagues, thermoelasticity studies suggests that these polypeptide elastomers are dominantly entropic elastomers above the temperature of the inverse temperature transition. A central question becomes the source of the entropic elastomeric force. On stretching, hydrophobic side chains become exposed to water, resulting in an exothermic reaction of hydrophobic hydration. The issue addressed by the present report is whether this decrease in solvent entropy on stretching might make a major contribution to the entropic elastomeric restoring force. It has previously been argued that the free energy of solvation can be made very small by a 30% ethylene glycol (EG):70% water solvent mixture. This is demonstrated here using the repeating pentapeptide sequence of elastin (Val{sup 1}-Pro{sup 2}-Gly{sup 3} -Val{sup 4}-Gly{sup 5}){sub n} or poly(VPGVG) and its {gamma}-irradiation cross-linked elastomeric matrix. Differential scanning calorimetry of the inverse temperature transition of poly(VPGVG) shows the endothermic heat of the transition to become very small in EG/H{sub 2}O when compared with H{sub 2}O alone, which also indicates a very small entropy change for the transition on exposure of the hydrophobic side chains to the EG/H{sub 2}O solvent mixture. A similar result is found for the crosslinked elastomeric matrix. Significantly, however, in spite of the lower heats for hydrophobic solvation, the elastic modulus and the entropic elastomeric forces generated are greater in EG/H{sub 2}O.
What the ultimate polymeric electro-optic materials will be: guest-host, crosslinked, or side-chain?
NASA Astrophysics Data System (ADS)
Zhang, Cheng; Zhang, Hua; Oh, Min-Cheol; Dalton, Larry R.; Steier, William H.
Material processing and device fabrication of many different electro-optic (EO) polymers developed at USC are reviewed. Detailed discussion is given to guest-host CLD/APCs, crosslinking perfluorocyclobutane (PFCB) polymer CX1, and thermally stable side-chain polymers CX2 and CX3. Excellent EO performance (1.4V at 1.31 μm, 2.1 V at 1.55 μm) was achieved in CLD/APC Mach-Zehnder modulators (2-cm, push-pull). CLD/APCs also possess low optical losses (1.2 dB/cm in slab waveguides and in thick core channel waveguides). However, the guest-host materials only have limited thermal stability (110-132 °C in short term, <60 °C in long term) and require special techniques in device fabrication. The crosslinking polymer CX1 was able to provide long-term stability at 85 oC when fully cured. It also has a low optical loss (comparable to CLD/APCs) before curing and decent EO coefficient when poled at 180 °C. However, after the films were poled at the crosslinking temperatures (200 °C or above), the transmissions of the waveguides and EO activity became very poor due to poling-induced chromophore degradation. By judicial molecular design of both chromophore and monomer structures to suppress thermal motion of polymer segments, we were able to realize the same or even better thermal stability in side-chain polymers CX2 and CX3. Since no curing is needed, devices can be poled at their optimal poling temperatures, and all good properties can be obtained simultaneously. Despite the excellent solubility in chlorinated solvents, these side-chain polymers are resistant to some other organic solvents or solutions such as acetone, photoresist and various UV-curable liquids.
Side-chain effects on electronic structure and molecular stacking arrangement of PCBM spin-coated films
NASA Astrophysics Data System (ADS)
Bazylewski, Paul F.; Kim, Kyung Hwan; Forrest, Jay L.; Tada, Hirokazu; Choi, Dong Hoon; Chang, Gap Soo
The electronic structure and molecular stacking arrangement of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) was studied using a combination of near-edge X-ray absorption fine structure measurements and density functional theory calculations. Measurements show that the side chain lifts the energy degeneracy of the C60 molecular orbitals around the chain attachment. This breaks the orbital symmetry of the LUMO of the C60 backbone which is observed through polarization dependence of C 1s → π∗ transitions. This dependence is analyzed to determine the bulk crystal structure of PCBM. X-ray emission and absorption measurements indicate the band gap energy of PCBM to be 1.87 eV.
Electron Correlation Effects and Nonlinear Optical Properties of Conjugated Linear and Cyclic Chains.
NASA Astrophysics Data System (ADS)
Cai, Yong-Ming
Reduced dimensionality and quantum confinement place special constraints on electronic excitations that result in unusually large nonlinear optical responses. One major purpose of this study is to provide an experimental basis for the development of a comprehensive microscopic description of the many-electron origin of the second order virtual excitation processes in quasi-one dimensional linear and cyclic chain structures. The experimental results were compared with the calculated results from configuration interaction theory for the magnitude, sign, and dispersion of beta_{rm ijk}( omega_3; omega_1,omega _2). DC field induced second harmonic generation (DCSHG) measurements of molecular units in liquid and gas phases have been performed over a broad frequency range extending from the near infrared through the visible. An infinite dilution extrapolation method which required combined experimental studies of DCSHG, dielectric constant, index of refraction, and specific volume has been employed. Theoretical gas phase values of beta_{rm ijk} can then be compared to experimental infinite dilution values. The DCSHG experimental methodology and techniques receive extensive review in this thesis in addition to the description of a new gas phase measurement.
The Role of Morphology and Electronic Chain Aggregation on the Optical Gain Properties of Semiconducting Conjugated Polymers
NASA Astrophysics Data System (ADS)
Lampert, Zachary Evan
Conjugated polymers (CPs) are a novel class of materials that exhibit the optical and electrical properties of semiconductors while still retaining the durability and processability of plastics. CPs are also intrinsically 4-level systems with high luminescence quantum efficiencies making them particularly attractive as organic gain media for solid-state laser applications. However, before CPs can emerge as a commercially available laser technology, a more comprehensive understanding of the morphological dependence of the photophysics is required. In this thesis, the morphology and chain conformation dependence of amplified spontaneous emission (ASE) and optical gain in thin films of poly[2-methoxy-5-(2'-ethylhexyloxy)-p-phenylene vinylene] (MEH-PPV) was investigated. By changing the chemical nature of the solvent from which films were cast, as well as the temperature at which films were annealed, CP films with different morphologies, and hence different degrees of interchain interactions were achieved. Contrary to the common perception that polymer morphology plays a decisive role in determining the ASE behavior of thin CP films, we found that chromophore aggregation and degree of conformational order have minimal impact on optical gain. In fact, experimental results indicated that an extremely large fraction of interchain aggregate species and/or exciton dissociating defects are required to significantly alter the optical properties and suppress stimulated emission. These results are pertinent to the fabrication and optimization of an electrically pumped laser device, as improvements in charge carrier mobility through controlled increases in chain aggregation may provide a viable means of optimizing injection efficiency without significantly degrading optical gain. To offset charge-induced absorption losses under electrical pumping, and to enable the use of more compact and economical sources under optical pumping, conjugated polymers exhibiting low lasing
Structure-guided optimization of estrogen receptor binding affinity and antagonist potency of pyrazolopyrimidines with basic side chains.
Zhou, H.; Sheng, S.; Compton, D.; Kim, Y.; Joachimiak, A.; Sharma, S.; Carlson, K.; Katzenellenbogen, B.; Nettles, K.; Greene, G.; Katzenellenbogen, J.; Biosciences Division; Univ. of Illinois; Univ. of Chicago; The Scripps Research Inst.
2,3-Diarylpyrazolo[1,5-a]pyrimidines are estrogen receptor (ER) antagonists of modest potency that we have described previously. Guided by the crystal structure of an ER-ligand complex that we have obtained with one of these compounds, we prepared analogs that contain a basic side chain at the 2- or 3-aryl group and quickly found one that, according to the structure-based prediction, shows an increase in binding affinity and antagonist potency and a loss of residual agonist activity.
Solvation free energies in [bmim]-based ionic liquids: Anion effect toward solvation of amino acid side chain analogues
NASA Astrophysics Data System (ADS)
Latif, Muhammad Alif Mohammad; Micaêlo, Nuno; Abdul Rahman, Mohd Basyaruddin
Stochastic molecular dynamics simulations were performed to investigate the solvation free energy of 15 neutral amino acid side chain analogues in aqueous and five, 1-butyl-3-methylimidazolium ([BMIM])-based ionic liquids. The results in aqueous were found highly correlated with previous experimental and simulation data. Meanwhile, [BMIM]-based RTILs showed better solvation thermodynamics than water to an extent that they were capable of solvating molecules immiscible in water. Non-polar analogues showed stronger solvation in hydrophobic RTIL anions such as [PF6]- and [Tf2N]- while polar analogues showed stronger solvation in the more hydrophilic RTIL anions such as [Cl]-, [TfO]- and [BF4]-.
Molecular engineering of side-chain liquid crystalline polymers by living cationic polymerization using Webster`s initiating system
Percec, V.
Webster`s cationic initiating system (HO{sub 3}SCF{sub 3}/SMe{sub 2}) (Macromolecules, 23, 1918 (1990)) was shown by us (for a review see Adv. Mater., 4, 548 (1992)) to polymerize, via a living mechanism, mesogenic vinyl ethers which contain a large variety of functional groups. This is mostly because SMe{sub 2} is a softer nucleophile than any of the functional groups available in these monomers. The molecular engineering of side-chain liquid crystalline polymers with conventional and complex architectures via this polymerization technique will be discussed.
Suppression of pancreatic tumor growth by targeted arsenic delivery with anti-CD44v6 single chain antibody conjugated nanoparticles.
Qian, Chenchen; Wang, Yong; Chen, Yinting; Zeng, Linjuan; Zhang, Qiubo; Shuai, Xintao; Huang, Kaihong
Arsenic trioxide (As2O3) is a promising anticancer agent for solid tumors. However, the high toxicity to normal tissues resulting from the lack of tumor specificity remains a huge challenge in its systemic application. Targeted vectors enabling drug delivery to specific cancer cells bring about great potential for better therapeutic efficacy whereas low side effects in cancer treatments. Our previous work has demonstrated that the anti-CD44v6 single chain variable fragment (scFv(CD44v6)) screened out from the human phage-displayed scFv library possesses high specificity and affinity to membrane antigen CD44v6 over-expressing in a subset of epithelium-derived cancers, such as pancreatic, hepatocellular, colorectal and gastric cancers. Herein, a maleimide-functionalized amphiphilic diblock copolymer of poly (ethylene glycol) and poly (D, L-lactide) (mal-PEG-PDLLA) was synthesized and assembled to vesicles with arsenite ion (As) encapsulated in their cores (As-NPs). Conjugation of scFv(CD44v6) with mal-PEG-PDLLA (scFv-As-NPs) enabled more efficient delivery of As and exhibited higher cytotoxic activity than non-targeted ones (As-NPs) in human pancreatic cancer cells PANC-1. Furthermore, the targeted delivery of As induced more significant gene suppression in terms of the expression of anti-apoptotic Bcl-2 protein. Consequently, the expression level of cleaved caspase-3 which is a molecular indicator of cell apoptosis was remarkably elevated. In animal tests, scFv-As-NPs were found to greatly increase accumulation of drug in tumor site and potentiate the efficacy of As in inhibiting tumor growth owing to the enhanced cell apoptosis. These results imply that our tumor specific nanocarriers provide a highly efficient and safe platform for pancreatic cancer therapy. PMID:23721794
Comprehensive Study on the Impact of the Cation Alkyl Side Chain Length on the Solubility of Water in Ionic Liquids
Kurnia, Kiki A.; Neves, Catarina M. S. S.; Freire, Mara G.; Santos, Luís M. N. B. F.; Coutinho, João A. P.
A comprehensive study on the phase behaviour of two sets of ionic liquids (ILs) and their interactions with water is here presented through combining experimental and theoretical approaches. The impact of the alkyl side chain length and the cation symmetry on the water solubility in the asymmetric [CN-1C1im][NTf2] and symmetric [CN-1CN-1im][NTf2] series of ILs (N up to 22), from 288.15 K to 318.15 K and at atmospheric pressure, was studied. The experimental data reveal that the solubility of water in ILs with an asymmetric cation is higher than in those with the symmetric isomer. Several trend shifts on the water solubility as a function of the alkyl side chain length were identified, namely at [C6C1im][NTf2] for asymmetric ILs and at [C4C4im][NTf2] and [C7C7im][NTf2] for the symmetric ILs. To complement the experimental data and to further investigate the molecular-level mechanisms behind the dissolution process, Density Functional Theory calculations, using the Conductor-like Screening Model for Real Solvents (COSMO-RS) and the Electrostatic potential-derived CHelpG, were performed. The COSMO-RS model is able to qualitatively predict water solubility as function of temperature and alkyl chain lengths of both symmetric and asymmetric cations. Furthermore, the model is also capable to predict the somewhat higher water solubility in the asymmetric cation, as well as the trend shift as function of alkyl chain lengths experimentally observed. Both COSMO-RS and the electrostatic potential-derived CHelpG show that the interactions of water and the IL cation take place on the IL polar region, namely on the aromatic head and adjacent methylene groups what explains the differences in water solubility observed for cations with different chain lengths. Furthermore, the CHelpG calculations for the isolated cations in the gas phase indicates that the trend shift of water solubility as function of alkyl chain lengths and the difference of water solubility in symmetric may also
Antiallergic activity of rosmarinic acid esters is modulated by hydrophobicity, and bulkiness of alkyl side chain.
Zhu, Fengxian; Xu, Zhongming; Yonekura, Lina; Yang, Ronghua; Tamura, Hirotoshi
Methyl, propyl and hexyl esters of rosmarinic, caffeic and p-coumaric acids were tested for antiallergic activity, and rosmarinic acid propyl ester exhibited the greatest β-hexosaminidase release suppression (IC50, 23.7 μM). Quadratic correlations between pIC50 and cLogP (r(2) = 0.94, 0.98, and 1.00, respectively) were observed in each acid ester series. The antiallergic activity is modulated by hydrophobicity, and alkyl chain bulkiness. PMID:25686361
Heterogeneous side chain conformation highlights a network of interactions implicated in hysteresis of the knotted protein, minimal tied trefoil
NASA Astrophysics Data System (ADS)
Burban, David J.; Haglund, Ellinor; Capraro, Dominique T.; Jennings, Patricia A.
Hysteresis is a signature for a bistability in the native landscape of a protein with significant transition state barriers for the interconversion of stable species. Large global stability, as in GFP, contributes to the observation of this rare hysteretic phenomenon in folding. The signature for such behavior is non-coincidence in the unfolding and refolding transitions, despite waiting significantly longer than the time necessary for complete denaturation. Our work indicates that hysteresis in the knotted protein, the minimal tied trefoil from Thermotoga maritma (MTTTm), is mediated by a network of side chain interactions within a tightly packed core. These initially identified interactions include proline 62 from a tight β-like turn, phenylalanine 65 at the beginning of the knotting loop, and histidine 114 that initiates the threading element. It is this tightly packed region and the knotting element that we propose is disrupted with prolonged incubation in the denatured state, and is involved in the observed hysteresis. Interestingly, the disruption is not linked to backbone interactions, but rather to the packing of side chains in this critical region.
Crystallographic studies of V44 mutants of Clostridium pasteurianum rubredoxin: Effects of side-chain size on reduction potential
Park, Il Yeong; Eidsness, Marly K.; Lin, I-Jin; Gebel, Erika B.; Youn, Buhyun; Harley, Jill L.; Machonkin, Timothy E.; Frederick, Ronnie O.; Markley, John L.; Smith, Eugene T.; Ichiye, Toshiko; Kang, ChulHee
Understanding the structural origins of differences in reduction potentials is crucial to understanding how various electron transfer proteins modulate their reduction potentials and how they evolve for diverse functional roles. Here, the high-resolution structures of several Clostridium pasteurianum rubredoxin (Cp Rd) variants with changes in the vicinity of the redox site are reported in order to increase this understanding. Our crystal structures of [V44L] (at 1.8 {angstrom} resolution), [V44A] (1.6 {angstrom}), [V44G] (2.0 {angstrom}) and [V44A, G45P] (1.5 {angstrom}) Rd (all in their oxidized states) show that there is a gradual decrease in the distance between Fe and the amide nitrogen of residue 44 upon reduction in the size of the side chain of residue 44; the decrease occurs from leucine to valine, alanine or glycine and is accompanied by a gradual increase in their reduction potentials. Mutation of Cp Rd at position 44 also changes the hydrogen-bond distance between the amide nitrogen of residue 44 and the sulfur of cysteine 42 in a size-dependent manner. Our results suggest that residue 44 is an important determinant of Rd reduction potential in a manner dictated by side-chain size. Along with the electric dipole moment of the 43-44 peptide bond and the 44-42 NHS type hydrogen bond, a modulation mechanism for solvent accessibility through residue 41 might regulate the redox reaction of the Rds. Proteins 2004.
First observation of amino acid side chain dynamics in membrane proteins using high field deuterium nuclear magnetic resonance spectroscopy
Kinsey, R.A.; Kintanar, A.; Tsai, M.D.; Smith, R.L.; Janes, N.; Oldfield, E.
The first deuterium NMR spectra of an individual membrane protein, bacteriohodopsin in the purple membrane of Halobacterium halobium R1 has been obtained. Biosynthetic isotopic enrichment with (gamma-2H6) valine and high field Fourier transform operation permitted rapid data acquisition on intact membranes, including measurement of relaxation times. At some temperatures high quality spectra could be obtained in less than 1 s. (U-14C)Valine tracer studies indicate that less than or equal to 2% of valine added to the growth medium is broken down and incorporated into other membrane constituents. The NMR results indicate that the valine side chain is a rather rigid structure. Motion about C alpha-C beta is slow (less than 10(5) s-1) at growth temperature, while motion about C beta-C gamma is as expected fast (much greater than 10(5) s-1) at all accessible temperatures. The activation energy for methyl group rotation from spin-lattice relaxation data between -75 and 53 degrees C is approximately 2.4 kcal/mol, in good agreement with previous 1H NMR studies on solid alkanes. Preliminary data on (gamma-2H6)valine-labeled Acholeplasma laidlawii B (PG9) cell membranes are also presented. Results strongly suggest that it should now be possible to observe in great detail the motions of any type of amino acid side chain in membrane proteins, including the effects of lipid composition on protein dynamics.
Aromatic substituents for prohibiting side-chain packing and π-π stacking in tin-cored tetrahedral stilbenoids
NASA Astrophysics Data System (ADS)
Kim, Cheolmin; Yoon, Min-Ju; Hong, Seok Hee; Park, Minjoon; Park, Kwangyong; Kim, Soo Young
Tetrahedral structures comprising Sn-cored materials with five different types of substituents were synthesized. For the substituents, we employed methyl and tert-butyl as aliphatic groups, and naphthyl and phenyl as aromatic groups. The bandgap is in the range of 3.28 - 3.56 eV. The All the compounds with substituents showed bathochromical photoluminescence characteristics and exhibited aggregation-induced emission characteristics. Specifically, the compounds with aromatic substituents prohibited side-chain packing and π-π stacking. The energy levels of the highest occupied and lowest unoccupied molecular orbitals were measured to be 5.5 - 5.75 and 2.0 - 2.37 eV, respectively. The maximum luminance efficiencies and power efficiencies of the Sn-cored compound-based organic light-emitting diodes (OLEDs) were 0.38 - 0.71 cd/A and 0.15 - 0.28 lm/W. Therefore, it is expected that Sn-cored compounds with a tetrahedral structure, especially those containing aromatic substituents, can be used as an active material in blue OLEDs for prohibiting side-chain packing and π-π stacking. [Figure not available: see fulltext.
The power of hard-sphere models for proteins: Understanding side-chain conformations and predicting thermodynamic stability
NASA Astrophysics Data System (ADS)
Zhou, Alice; O'Hern, Corey; Regan, Lynne
We seek to dramatically improve computational protein design using minimal models that include only the dominant physical interactions. By modeling proteins with hard-sphere interactions and stereochemical constraints, we are able to explain the side-chain dihedral angle distributions for Leu, Ile, and other hydrophobic residues that are observed in protein crystal structures. We also consider inter-residue interactions on the distribution of side-chain dihedral angles for residues in the hydrophobic core of T4 lysozyme. We calculate the energetic and entropic contributions to the free energy differences between wildtype T4 lysozyme and several mutants involving Leu to Ala substitutions. We find a strong correlation between the entropy difference and the decrease in the melting temperature of the mutatants. These results emphasize that considering both entropy and enthalpy is crucial for obtaining a quantitative understanding of protein stability. NSF DMR-1006537 and PHY-1019147, the Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences, and Howard Hughes Medical Institute International Research Fellowship
Triblock Copolymers with Grafted Fluorine-Free Amphiphilic Non-Ionic Side Chains for Antifouling and Fouling-Release Applications
Y Cho; H Sundaram; C Weinman; M Paik; M Dimitriou; J Finlay; M Callow; J Callow; E Kramer; C Ober
Fluorine-free, amphiphilic, nonionic surface active block copolymers (SABCs) were synthesized through chemical modification of a polystyrene-block-poly(ethylene-ran-butylene)-block-polyisoprene triblock copolymer precursor with selected amphiphilic nonionic Brij and other surfactants. Amphiphilicity was imparted by a hydrophobic aliphatic group combined with a hydrophilic poly(ethylene glycol) (PEG) group-containing moiety. The surfaces were characterized by dynamic water contact angle, atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and near edge X-ray absorption fine structure (NEXAFS) analysis. In biofouling assays, settlement (attachment) of both spores of the green alga Ulva and cells of the diatom Navicula on SABCs modified with Brij nonionic side chains was significantly reduced relative to a PDMS standard, with a nonionic surfactant combining a PEG group and an aliphatic moiety demonstrating the best performance. Additionally, a fouling-release assay using sporelings (young plants) of Ulva and Navicula suggested that the SABC derived from nonionic Brij side chains also out-performed PDMS as a fouling-release material. Good antifouling and fouling-release properties were not demonstrated for the other two amphiphilic surfaces derived from silicone and aromatic group containing nonionic surfactants included in this study. The results suggest that small differences in chemical surface functionality impart more significant changes with respect to the antifouling settlement and fouling-release performance of materials than overall wettability behavior.
Variation of the net charge, lipophilicity and side chain flexibility in Dmt1-DALDA: effect on opioid activity and biodistribution
Novoa, Alexandre; Van Dorpe, Sylvia; Wynendaele, Evelien; Spetea, Mariana; Bracke, Nathalie; Stalmans, Sofie; Betti, Cecilia; Chung, Nga N.; Lemieux, Carole; Zuegg, Johannes; Cooper, Matthew A.; Tourwé, Dirk; De Spiegeleer, Bart; Schiller, Peter W.; Ballet, Steven
The influence of the side chain charges of the second and fourth amino acid residues in the peptidic μ opioid lead agonist Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]-DALDA) was examined. Additionally, to increase the overall lipophilicity of [Dmt1]-DALDA and to investigate the Phe3 side chain flexibility, the final amide bond was N-methylated and Phe3 was replaced by a constrained aminobenzazepine analogue. The in vitro receptor binding and activity of the peptides, as well as their in vivo transport (brain in- and efflux and tissue biodistribution) and antinociceptive properties after peripheral administration (i.p. and s.c.) in mice were determined. The structural modifications result in significant shifts of receptor binding, activity and transport properties. Strikingly, while [Dmt1]-DALDA and its N-methyl analogue, Dmt-D-Arg-Phe-NMeLys-NH2, showed a long-lasting antinociceptive effect (>7h), the peptides with D-Cit2 generate potent antinociception more rapidly (maximal effect at 1h post-injection) but also lose their analgesic activity faster, when compared to [Dmt1]-DALDA and [Dmt1,NMeLys4]-DALDA. PMID:23102273
Heterogeneous side chain conformation highlights a network of interactions implicated in hysteresis of the knotted protein, minimal tied trefoil.
Burban, David J; Haglund, Ellinor; Capraro, Dominique T; Jennings, Patricia A
Hysteresis is a signature for a bistability in the native landscape of a protein with significant transition state barriers for the interconversion of stable species. Large global stability, as in GFP, contributes to the observation of this rare hysteretic phenomenon in folding. The signature for such behavior is non-coincidence in the unfolding and refolding transitions, despite waiting significantly longer than the time necessary for complete denaturation. Our work indicates that hysteresis in the knotted protein, the minimal tied trefoil from Thermotoga maritma (MTTTm), is mediated by a network of side chain interactions within a tightly packed core. These initially identified interactions include proline 62 from a tight β-like turn, phenylalanine 65 at the beginning of the knotting loop, and histidine 114 that initiates the threading element. It is this tightly packed region and the knotting element that we propose is disrupted with prolonged incubation in the denatured state, and is involved in the observed hysteresis. Interestingly, the disruption is not linked to backbone interactions, but rather to the packing of side chains in this critical region. PMID:26291198
Heterogeneous side chain conformation highlights a network of interactions implicated in hysteresis of the knotted protein, Minimal Tied Trefoil (MTTTm)
Capraro, Dominique T.; Jennings, Patricia A.
Hysteresis is a signature for a bistability in the native landscape of a protein with significant transition state barriers for the interconversion of stable species. Large global stability, as in GFP, contributes to the observation of this rare hysteretic phenomenon in folding. The signature for such behavior is non-coincidence in the unfolding and refolding transitions, despite waiting significantly longer than the time necessary for complete denaturation. Our work indicates that hysteresis in the knotted protein, the Minimal Tied Trefoil from Thermotoga maritma (MTTTm), is mediated by a network of side chain interactions within a tightly packed core. These initially identified interactions include proline 62 from a tight β-like turn, phenylalanine 65 at the beginning of the knotting loop, and histidine 114 that initiates the threading element. It is this tightly packed region and the knotting element that we propose is disrupted with prolonged incubation in the denatured state, and is involved in the observed hysteresis. Interestingly, the disruption is not linked to backbone interactions, but rather to the packing of side chains in this critical region. PMID:26291198
Synthesis and Photophysical Properties of Soluble Low-Bandgap Thienothiophene Polymers with Various Alkyl Side-Chain Lengths
Bae, W. J.; Scilla, C.; Duzhko, V. V.; Jo, Jang; Coughlin, E. B.
We report the facile synthesis and characterization of a class of thienothiophene polymers with various lengths of alkyl side chains. A series of 2-alkylthieno[3,4-b]thiophene monomers (Ttx) have been synthesized in a two-step protocol in an overall yield of 28–37%. Poly(2-alkylthieno[3,4-b]thiophenes) (PTtx, alkyl: pentyl, hexyl, heptyl, octyl, and tridecyl) were synthesized by oxidative polymerization with FeCl₃ or via Grignard metathesis (GRIM) polymerization methods. The polymers are readily soluble in common organic solvents. The polymers synthesized by GRIM polymerization method (PTtx-G) have narrower molecular weight distribution (Ð) with lower molecular weight (Mn) than those synthesized by oxidative polymerization (PTtx-O). The band structures of the polymers with various lengths of alkyl side chains were investigated by UV–vis spectroscopy, cyclic voltammetry, and ultraviolet photoelectron spectroscopy. These low-bandgap polymers are good candidates for organic transistors, organic light-emitting diodes, and organic photovoltaic cells.
Side chain variations radically alter the diffusion of poly(2-alkyl-2-oxazoline) functionalised nanoparticles through a mucosal barrier.
Mansfield, Edward D H; de la Rosa, Victor R; Kowalczyk, Radoslaw M; Grillo, Isabelle; Hoogenboom, Richard; Sillence, Katy; Hole, Patrick; Williams, Adrian C; Khutoryanskiy, Vitaliy V
Functionalised nanomaterials are gaining popularity for use as drug delivery vehicles and, in particular, mucus penetrating nanoparticles may improve drug bioavailability via the oral route. To date, few polymers have been investigated for their muco-penetration, and the effects of systematic structural changes to polymer architectures on the penetration and diffusion of functionalised nanomaterials through mucosal tissue have not been reported. We investigated the influence of poly(2-oxazoline) alkyl side chain length on nanoparticle diffusion; poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), and poly(2-n-propyl-2-oxazoline) were grafted onto the surface of thiolated silica nanoparticles and characterised by FT-IR, Raman and NMR spectroscopy, thermogravimetric analysis, and small angle neutron scattering. Diffusion coefficients were determined in water and in a mucin dispersion (using Nanoparticle Tracking Analysis), and penetration through a mucosal barrier was assessed using an ex vivo fluorescence technique. The addition of a single methylene group in the side chain significantly altered the penetration and diffusion of the materials in both mucin dispersions and mucosal tissue. Nanoparticles functionalised with poly(2-methyl-2-oxazoline) were significantly more diffusive than particles with poly(2-ethyl-2-oxazoline) while particles with poly(2-n-propyl-2-oxazoline) showed no significant increase compared to the unfunctionalised particles. These data show that variations in the polymer structure can radically alter their diffusive properties with clear implications for the future design of mucus penetrating systems. PMID:27400181
The synthesis and imaging study of a series of novel photoactive polymers with diazoketo groups in their side chains
NASA Astrophysics Data System (ADS)
Liu, Lu; Zou, Yingquan; Yang, Yuchun; Huang, Yong; Liu, Qisheng; Niu, Huinan
A kind of photoactive polymer with diazoketo groups in its side chains has been reported in SPIE and other related papers, and this photoactive polymer can be used in deep UV non-CARs (non-chemically amplified resists) system. Based on the work above, a series of novel photoactive monomers with substituents like phenyl, p-methylphenyl, p-methoxyphenyl, p-dimethylaminophenyl on the end of the molecule are designed and synthesized. By changing their substituents, the maximum-absorption wavelength of the photoactive monomers has been moved to 356nm, and it still has comparatively large absorption at 365nm (I-line). A series of photoactive polymers were obtained by polymerizing the monomer with methyl methacrylate and 2-hydroxyethyl methacrylate together. Upon irradiaton in the waveleng of 365nm, the diazoketo groups which are in the side chains of the photoactive polymers undergo the wolff rearrangment and afford ketens that react with water to provide base-soluble photoproducts. Applying this kind of photoactive polymers to non-CARs, a positive image can be obtained. This kind of photoactive polymers have great value in I-line non-CARs, TFT-LCD and IC discrete devices processing. And its anti-dry etching ability is enhanced by the introduction of the benzene ring.
Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection
Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclometalated ruthenium catalysts has led to new strategies for achieving such control with high fidelity and Z selectivity, but the scope and limitations of these catalysts on substrates bearing multiple functionalities, including peptides, remained unexplored. Herein, we report an assessment of various factors that contribute to both productive and nonproductive Z-selective metathesis on peptides. The influence of sterics, side-chain identity, and preorganization through peptide secondary structure are explored by homodimerization, cross metathesis, and ring-closing metathesis. Our results indicate that the amino acid side chain and identity of the olefin profoundly influence the activity of cyclometalated ruthenium catalysts in Z-selective metathesis. The criteria set forth for achieving high conversion and Z selectivity are highlighted by cross metathesis and ring-closing metathesis on diverse peptide substrates. The principles outlined in this report are important not only for expanding the scope of Z-selective olefin metathesis to peptides but also for applying stereoselective olefin metathesis in general synthetic endeavors. PMID:25102124
Fourier transform microwave spectroscopy of Ac-Ser-NH2: the role of side chain interactions in peptide folding.
Cabezas, Carlos; Robben, Martinus A T; Rijs, Anouk M; Peña, Isabel; Alonso, J L
Serine capped dipeptide N-acetyl-l-serinamide (Ac-Ser-NH2) has been investigated using Fourier transform microwave spectroscopic techniques combined with laser ablation sources. Spectral signatures originating from one dominant species have been detected in the supersonic expansion. Rotational and nuclear quadrupole coupling constants of the two (14)N nuclei have been used in the characterization of a C/γ-turn structure, which is stabilized by a CO∙∙∙HN intramolecular hydrogen bond closing a seven-membered ring. Two extra hydrogen bonds involving the polar side chain (-CH2OH) further stabilize the structure. The non-observation of C5 species, attributed to the presence of the polar side chain, is in contrast with the previous gas phase observation of the related dipeptides containing glycine or alanine residues. The A-E splitting pattern arising from the internal rotation of the methyl group has been analyzed and the internal rotation barrier has been determined. PMID:26186259
Scaffolding of peptides using a coarse-grained representation of residues with side chain and backbone nodes
NASA Astrophysics Data System (ADS)
Pandey, Ras; Farmer, Barry
Monte Carlo simulations are performed to study scaffolding of peptides (KSL) on a cubic lattice. A residue is represented by three backbone nodes (C-terminal, C-alpha, N-terminal) and a side node connected to the central C-alpha node each connected by fluctuating bond. A peptide is a chain of residues. A solvent constituent is represented by a particle of the same size as that of a node. Peptides and solvent are distributed randomly in the cubic box with concentration Cp and Cw respectively. Each residue interacts with other residues and solvent particles via its side chain with the Lennard-Jones (LJ) potential where a knowledge-based interaction matrix is used for the residue-residue interaction. We examine local and global physical quantities such as mobility and energy of each residue, radial distribution function, and structure factor. We find that the scaffolding of peptides depends on the interaction strength and concentration of the solvent. The structure factor shows multi-scale structure of the aggregates. This work is supported by the Air Force Research Laboratory.
Effect of heteroatom insertion at the side chain of 5-alkyl-1H-tetrazoles on their properties as catalysts for ester hydrolysis at neutral pH.
Bhattacharya, Santanu; Vemula, Praveen Kumar
[reaction: see text] Herein we introduce tetrazole and its suitably designed derivatives as powerful ester-cleaving reagents. By first performing a detailed ab initio computational study, we found that, in the side chain of 5-alkyl-1H-tetrazoles, introduction of a heteroatom (e.g., N, O, or S at the alpha-position of the tetrazole ring) raises the charge on the tetrazole nucleus significantly. All calculations have been performed using restricted Hartree-Fock (RHF) and hybrid ab initio/DFT (B3LYP) methods employing 6-31G* and 6-31+G* basis sets. To estimate the nucleophilicity of these reagents, the charges on conjugate bases of various tetrazole derivatives have been calculated using natural population (NBO) analysis in gas phase and in water. Free energy of protonation (fep) of the 1H-tetrazole derivatives (1-7), free energy of solvation, deltaG(aq), and the corresponding pKa values have been calculated by self-consistent reaction field (SCRF) methods applying the polarized continuum model (PCM). Since the calculation indicates that incorporation of heteroatom leads to enhanced nucleophilicity in their deprotonated anionic tetrazole forms, a series of 5-substituted 1H-tetrazole derivatives have been synthesized. These compounds indeed catalyze the hydrolysis of p-nitrophenyl diphenyl phosphate (PNPDPP) and p-nitrophenyl hexanoate (PNPH) efficiently in cationic cetyl trimethylammonium bromide (CTABr) micelles at pH 7.0 and 25 degrees C. The pseudo-first-order rate constants (k(obs)) were determined for each catalyst against both substrates. The experimental and theoretical results show that, to achieve better k(obs) values for the cleavage of PNPDPP and PNPH under micellar conditions, charge on the N- atom (nucleophile) of conjugate base is important. Replacing the alpha-CH2 in alkyl substituent with S (3), NH (4), or O (5) enhances the accumulation of charge on N- in conjugate bases of tetrazoles and subsequently increases their intrinsic nucleophilic reactivity
New Insights into the Structure of (1→3,1→6)-β-D-Glucan Side Chains in the Candida glabrata Cell Wall
Lowman, Douglas W.; West, Lara J.; Bearden, Daniel W.; Wempe, Michael F.; Power, Trevor D.; Ensley, Harry E.; Haynes, Ken; Williams, David L.; Kruppa, Michael D.
β-glucan is a (1→3)-β-linked glucose polymer with (1→6)-β-linked side chains and a major component of fungal cell walls. β-glucans provide structural integrity to the fungal cell wall. The nature of the (1–6)-β-linked side chain structure of fungal (1→3,1→6)-β-D-glucans has been very difficult to elucidate. Herein, we report the first detailed structural characterization of the (1→6)-β-linked side chains of Candida glabrata using high-field NMR. The (1→6)-β-linked side chains have an average length of 4 to 5 repeat units spaced every 21 repeat units along the (1→3)-linked polymer backbone. Computer modeling suggests that the side chains have a bent curve structure that allows for a flexible interconnection with parallel (1→3)-β-D-glucan polymers, and/or as a point of attachment for proteins. Based on these observations we propose new approaches to how (1→6)-β-linked side chains interconnect with neighboring glucan polymers in a manner that maximizes fungal cell wall strength, while also allowing for flexibility, or plasticity. PMID:22096604
Reduced mucosal side-effects of acetylsalicylic acid after conjugation with tris-hydroxymethyl-aminomethane. Synthesis and biological evaluation of a new anti-inflammatory compound.
Varga, Gabriella; Lajkó, Norbert; Ugocsai, Melinda; Érces, Dániel; Horváth, Gyöngyi; Tóth, Gábor; Boros, Mihály; Ghyczy, Miklós
Acetylsalicylic acid (ASA) causes adverse haemorrhagic reactions in the upper gastrointestinal (GI) tract, and previous results have suggested that combination therapy with 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) could provide protection in this scenario. Based on this hypothesis, our aim was to develop a new compound from ASA and Tris precursors and to characterize the biological effects of ASA-Tris and the derivatives ASA-bis- and mono-hydroxymethyl-aminomethane (ASA-Bis, ASA-Mono, respectively) using in vivo and in vitro test systems. ASA or ASA conjugates (0.55mmol/kg, each) were administered intragastrically to Sprague-Dawley rats. Changes in the mucosal structure and in the serosal microcirculation were detected by in vivo imaging techniques, the plasma TNF-alpha, tissue xanthine oxidoreductase and myeloperoxidase activities, and liver cytochrome c changes were also determined. In two separate series, platelet aggregation and carrageenan arthritis-induced inflammatory pain were measured in control, ASA and ASA-Tris-treated groups. Severe mucosal injury and a significant decrease in serosal red blood cell velocity developed in the ASA-treated group and an ~2-fold elevation in proinflammatory mediator levels evolved. ASA-Tris did not cause bleeding, microcirculatory dysfunction, mucosal injury or an elevation in proinflammatory markers. The ASA-Mono and ASA-Bis conjugates did not cause macroscopic bleeding, but the inflammatory activation was apparent. ASA-Tris did not influence the cyclooxygenase-induced platelet aggregation significantly, but the inflammatory pain was reduced as effectively as in the case of equimolar ASA doses. ASA-Tris conjugation is an effective approach through which the GI side-effects of ASA are controlled by decreasing the cytokine-mediated progression of pro-inflammatory events. PMID:27079640
Synthesis and characterization of side-chain cholesterol derivatives based on double bond
NASA Astrophysics Data System (ADS)
Yu, Yun-Long; Bai, Jun-Wei; Zhang, Jun-Hua
After steps of esterification, epoxidation and ring-opening, a series of novel monomers of 5-hydroxyl-6-methacryloyloxy-3-alkylate, CnCOOCh (n = 1, 2, 3, 4, 5) were synthesized. After that, the corresponding polymers (PnCOOCh, n = 1, 2, 3, 4, 5) were obtained by free radical polymerization. The molecular structure, composition and thermal behaviors of monomers and polymers were confirmed by 1H NMR, FTIR, single crystal diffractometer, GPC, DSC and TGA. The results indicate that although their molecular weights are not high, all the polymers have high glass transition (Tg) and degradation temperature. In addition, Tg gradually decreases with increasing of alkyl chain lengths, and the degradation temperature increases with the increase of carbon number.
Alcohol- and water-soluble bis(tpy)quaterthiophenes with phosphonium side groups: new conjugated units for metallo-supramolecular polymers.
Štenclová, P; Šichová, K; Šloufová, I; Zedník, J; Vohlídal, J; Svoboda, J
Bis(tpy)quaterthiophenes with symmetrically distributed two and four 6-bromohexyl side groups were prepared and modified by the reaction with triethylphosphine to give the corresponding ionic species. Both ionic and non-ionic bis(tpy)quaterthiophenes (unimers) were assembled with Zn(2+) and Fe(2+) ions to conjugated metallo-supramolecular polymers (MSPs), of which the ionic ones are soluble in alcohols and those derived from tetrasubstituted unimers are soluble even in water. The differences in assembly are specified between systems with (i) ionic and non-ionic unimers, (ii) Zn(2+) and Fe(2+) ion couplers, and (iii) methanol and water solvents. A substantial decrease in the stability of Fe-MSPs and a surprisingly high red shift of the luminescence band of Zn-MSPs were observed on going from methanol to aqueous solutions. PMID:26667325
Medium-chain triglycerides and conjugated linoleic acids in beverage form increase satiety and reduce food intake in humans.
Coleman, Hannah; Quinn, Paul; Clegg, Miriam E
Both developed and developing countries are seeing increasing trends of obesity in people young and old. It is thought that satiety may play a role in the prevention of obesity by increasing satiety and reducing energy intake. We hypothesized that medium-chain triglycerides (MCT) would increase satiety and decrease food intake compared with conjugated linoleic acid (CLA) and a control oil. Nineteen healthy participants were tested on 3 separate occasions, where they consumed a beverage test breakfast containing (1) vegetable oil (control), (2) CLA, or (3) MCT. Participants self-requested an ad libitum sandwich buffet lunch. Time between meals, satiety from visual analog scales, energy intake at lunch, and intake for the rest of the day using weighed food diaries were measured. The results indicated that the time until a meal request was significantly different between the 3 meals (P=.016); however, there were no differences in intakes at the ad libitum lunch (P>.05). The CLA breakfast generated the greatest delay in meal time request. There was a difference between the control lipid compared with both the CLA and MCT for energy intake over the remainder of the test day and for total energy intake on the test day (P<.001 for both), with the CLA and MCT resulting in a lower intake than the control throughout the day. There were no significant differences in satiety from visual analog scale scores (P>.05). Both CLA and MCT increased satiety and reduced energy intake, indicating a potential role in aiding the maintenance of energy balance. PMID:27188898
Simple physics-based analytical formulas for the potentials of mean force for the interaction of amino acid side chains in water. 3. Calculation and parameterization of the potentials of mean force of pairs of identical hydrophobic side chains.
Makowski, Mariusz; Sobolewski, Emil; Czaplewski, Cezary; Liwo, Adam; Ołdziej, Stanisław; No, Joo Hwan; Scheraga, Harold A
The potentials of mean force of homodimers of the molecules modeling hydrophobic amino acid side chains (ethane (for alanine), propane (for proline), isobutane (for valine), isopentane (for leucine and isoleucine), ethylbenzene (for phenylalanine), and methyl propyl sulfide (for methionine)) were determined by umbrella-sampling molecular dynamics simulations in explicit water as functions of distance and orientation. Analytical expressions consisting of the Gay-Berne term to represent effective van der Waals interactions and the cavity term derived in paper 1 of this series were fitted to the potentials of mean force. The positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the orientation of the molecules, were well represented by the analytical expressions for all systems, which justifies use of such potentials in coarse-grain protein-folding simulations. PMID:17388418
The Effect of Side-Chain Length on the Solid-State Structure and Optical Properties of F8BT: A DFT Study
NASA Astrophysics Data System (ADS)
Javad Eslamibidgoli, Mohammad; Lagowski, Jolanta B.
Using the long-range corrected hybrid density functional theory (DFT/B97D) approach, we have performed bulk solid state calculations to investigate the influence of side-chain length on the molecular packing and optical properties of poly (9,9-di-n-octylfluorene-alt-benzothiadiazole) or F8BT. Two different packing structures, the lamellar and nearly hexagonal, were obtained corresponding to longer and shorter side-chains respectively. This behavior can be attributed to the micro-phase separations between the flexible side-chains and the rigid backbones and is in agreement with previous investigations for other hairy-rod polymers. In addition, as a result of the efficient inter-chain interactions for the lamellar structure, the dihedral angle between the F8 and BT units is reduced providing a more planar configuration for the backbone which leads to the decreased band gap (by 0.2-0.3 eV) in comparison to the hexagonal phase and the gas phase with no side-chain. Time-dependent DFT (TDDFT/B3LYP) was also used to study the excited states of the monomer of F8BT optimized in solid-state structures with different side-chain lengths. It is found that the absorption spectrum is red shifted for the polymers with lamellar structure relative to the polymers in hexagonal and gas phases.
Side chain mobility and ligand interactions of the G strand of tear lipocalins by site-directed spin labeling.
Glasgow, B J; Gasymov, O K; Abduragimov, A R; Yusifov, T N; Altenbach, C; Hubbell, W L
Side chain mobility, accessibility, and backbone motion were studied by site-directed spin labeling of sequential cysteine mutants of the G strand in tear lipocalins (TL). A nitroxide scan between residues 98 and 105 revealed the alternating periodicity of mobility and accessibility to NiEDDA and oxygen, characteristic of a beta-strand. Residue 99 was the most inaccessible to NiEDDA and oxygen. EPR spectra with the fast relaxing agent, K(3)Fe(CN)(6), exhibited two nitroxide populations for most residues. The motionally constrained population was relatively less accessible to K(3)Fe(CN)(6) because of dynamic tertiary contact, probably with side chain residues of adjacent strands. With increasing concentrations of sucrose, the spectral contribution of the immobile component was greater, indicating a larger population with tertiary contact. Increased concentrations of sucrose also resulted in a restriction of mobility of spin-labeled fatty acids which were bound within the TL cavity. The data suggest that sucrose enhanced ligand affinity by slowing the backbone motion of the lipocalin. The correlation time of an MTSL derivative (I) attached to F99C resulted in the lack of side chain motion and therefore reflects the overall rotation of the TL complex. The correlation time of F99C in tears (13.5 ns) was the same as that in buffer and indicates that TL exists as a dimer under native conditions. TL-spin-labeled ligand complexes have a shorter correlation time than the protein alone, indicating that the fatty acids are not rigidly anchored in the cavity, but move within the pocket. This segmental motion of the ligand was modulated by protein backbone fluctuations. Accessibility studies with oxygen and NiEDDA were performed to determine the orientation and depth of a series of fatty acid derivatives in the cavity of TL. Fatty acids are oriented with the hydrocarbon tail buried in the cavity and the carboxyl group oriented toward the mouth. In general, the mobility of the
Role of the Escherichia coli O157:H7 O side chain in adherence and analysis of an rfb locus.
Bilge, S S; Vary, J C; Dowell, S F; Tarr, P I
Shiga-toxigenic Escherichia coli strains belonging to serotype O157 are important human pathogens, but the genetic basis of expression of the O157 antigen and the role played by the lipopolysaccharide O side chain in the adherence of this organism to epithelial cells are not understood. We performed TnphoA mutagenesis on E. coli O157:H7 strain 86-24 to identify a mutant (strain F12) deficient in O-antigen expression. Nucleotide sequence analysis demonstrated that the transposon inserted within an open reading frame with significant homology to rfbE of Vibrio cholerae O1 (U. H. Stroeher, L. E. Karageorgos, R. Morona, and P. A. Manning, Proc. Natl. Acad. Sci. USA 89:2566-2570, 1992), which is postulated to encode perosamine synthetase. This open reading frame was designated rfbE(EcO157:H7). The guanine-plus-cytosine fraction (0.35) suggests that rfbE(EcO157:H7) may have originated in a species other than E. coli. rfbE(EcO157:H7) is conserved in nontoxigenic E. coli O157 strains expressing a variety of other flagellar antigens but is not found in E. coli O55:H7 strains, which are more closely related to E. coli O157:H7. Strain F12 was significantly more adherent to HeLa cells in a quantitative adherence assay than was its E. coli O157:H7 parent, but they did not differ in other phenotypes. Restoration of the expression of the O side chain by complementation of the TnphoA mutation in strain F12 by a plasmid expressing intact rfbE(EcO157:H7) reduced the adherence of the hyperadherent strain F12. We conclude that rfbE(EcO157:H7) is necessary for the expression of the O157 antigen, that acquisition of E. coli rfb genes occurred independently in E. coli O157:H7 and unrelated O157 strains, and that the O side chain of E. coli O157:H7 lipopolysaccharide interferes with the adherence of E. coli O157:H7 to epithelial cells. PMID:8890241
Side-chain hydrophobicity and the stability of Aβ16–22 aggregates
Berhanu, Workalemahu M; Hansmann, Ulrich H E
Recent mutagenesis studies using the hydrophobic segment of Aβ suggest that aromatic π-stacking interactions may not be critical for fibril formation. We have tested this conjecture by probing the effect of Leu, Ile, and Ala mutation of the aromatic Phe residues at positions 19 and 20, on the double-layer hexametric chains of Aβ fragment Aβ16–22 using explicit solvent all-atom molecular dynamics. As these simulations rely on the accuracy of the utilized force fields, we first evaluated the dynamic and stability dependence on various force fields of small amyloid aggregates. These initial investigations led us to choose AMBER99SB-ILDN as force field in multiple long molecular dynamics simulations of 100 ns that probe the stability of the wild-type and mutants oligomers. Single-point and double-point mutants confirm that size and hydrophobicity are key for the aggregation and stability of the hydrophobic core region (Aβ16–22). This suggests as a venue for designing Aβ aggregation inhibitors the substitution of residues (especially, Phe 19 and 20) in the hydrophobic region (Aβ16–22) with natural and non-natural amino acids of similar size and hydrophobicity. PMID:23015407
Probing the Carboxyester Side Chain in Controlled Deactivation (−)-Δ8-Tetrahydrocannabinols
We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (−)-Δ8-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain's polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action. PMID:25470070
Unraveling the Interplay of Backbone Rigidity and Electron Rich Side-Chains on Electron Transfer in Peptides: The Realization of Tunable Molecular Wires
Electrochemical studies are reported on a series of peptides constrained into either a 310-helix (1–6) or β-strand (7–9) conformation, with variable numbers of electron rich alkene containing side chains. Peptides (1 and 2) and (7 and 8) are further constrained into these geometries with a suitable side chain tether introduced by ring closing metathesis (RCM). Peptides 1, 4 and 5, each containing a single alkene side chain reveal a direct link between backbone rigidity and electron transfer, in isolation from any effects due to the electronic properties of the electron rich side-chains. Further studies on the linear peptides 3–6 confirm the ability of the alkene to facilitate electron transfer through the peptide. A comparison of the electrochemical data for the unsaturated tethered peptides (1 and 7) and saturated tethered peptides (2 and 8) reveals an interplay between backbone rigidity and effects arising from the electron rich alkene side-chains on electron transfer. Theoretical calculations on β-strand models analogous to 7, 8 and 9 provide further insights into the relative roles of backbone rigidity and electron rich side-chains on intramolecular electron transfer. Furthermore, electron population analysis confirms the role of the alkene as a "stepping stone" for electron transfer. These findings provide a new approach for fine-tuning the electronic properties of peptides by controlling backbone rigidity, and through the inclusion of electron rich side-chains. This allows for manipulation of energy barriers and hence conductance in peptides, a crucial step in the design and fabrication of molecular-based electronic devices. PMID:25122122
Effect of charged amino acid side chain length on lateral cross-strand interactions between carboxylate- and guanidinium-containing residues in a β-hairpin.
Kuo, Hsiou-Ting; Liu, Shing-Lung; Chiu, Wen-Chieh; Fang, Chun-Jen; Chang, Hsien-Chen; Wang, Wei-Ren; Yang, Po-An; Li, Jhe-Hao; Huang, Shing-Jong; Huang, Shou-Ling; Cheng, Richard P
β-Sheet is one of the major protein secondary structures. Oppositely charged residues are frequently observed across neighboring strands in antiparallel sheets, suggesting the importance of cross-strand ion pairing interactions. The charged amino acids Asp, Glu, Arg, and Lys have different numbers of hydrophobic methylenes linking the charged functionality to the backbone. To investigate the effect of side chain length of guanidinium- and carboxylate-containing residues on lateral cross-strand ion pairing interactions at non-hydrogen-bonded positions, β-hairpin peptides containing Zbb-Agx (Zbb = Asp, Glu, Aad in increasing length; Agx = Agh, Arg, Agb, Agp in decreasing length) sequence patterns were studied by NMR methods. The fraction folded population and folding energy were derived from the chemical shift deviation data. Peptides with high fraction folded populations involved charged residue side chain lengths that supported high strand propensity. Double mutant cycle analysis was used to determine the interaction energy for the potential lateral ion pairs. Minimal interaction was observed between residues with short side chains, most likely due to the diffused positive charge on the guanidinium group, which weakened cross-strand electrostatic interactions with the carboxylate side chain. Only the Aad-Arg/Agh interactions with long side chains clearly exhibited stabilizing energetics, possibly relying on hydrophobics. A survey of a non-redundant protein structure database revealed that the statistical sheet pair propensity followed the trend Asp-Arg < Glu-Arg, implying the need for matching long side chains. This suggested the need for long side chains on both guanidinium-bearing and carboxylate-bearing residues to stabilize the β-hairpin motif. PMID:25646959
Role of Side Chains in β-Sheet Self-Assembly into Peptide Fibrils. IR and VCD Spectroscopic Studies of Glutamic Acid-Containing Peptides.
Tobias, Fernando; Keiderling, Timothy A
Poly(glutamic acid) at low pH self-assembles after incubation at higher temperature into fibrils composed of antiparallel sheets that are stacked in a β2-type structure whose amide carbonyls have bifurcated H-bonds involving the side chains from the next sheet. Oligomers of Glu can also form such structures, and isotope labeling has provided insight into their out-of-register antiparallel structure [ Biomacromolecules 2013 , 14 , 3880 - 3891 ]. In this paper we report IR and VCD spectra and transmission electron micrograph (TEM) images for a series of alternately sequenced oligomers, Lys-(Aaa-Glu)5-Lys-NH2, where Aaa was varied over a variety of polar, aliphatic, or aromatic residues. Their spectral and TEM data show that these oligopeptides self-assemble into different structures, both local and morphological, that are dependent on both the nature of the Aaa side chains and growth conditions employed. Such alternate peptides substituted with small or polar residues, Ala and Thr, do not yield fibrils; but with β-branched aliphatic residues, Val and Ile, that could potentially pack with Glu side chains, these oligopeptides do show evidence of β2-stacking. By contrast, for Leu, with longer side chains, only β1-stacking is seen while with even larger Phe side chains, either β-form can be detected separately, depending on preparation conditions. These structures are dependent on high temperature incubation after reducing the pH and in some cases after sonication of initial fibril forms and reincubation. Some of these fibrillar peptides, but not all, show enhanced VCD, which can offer evidence for formation of long, multistrand, often twisted structures. Substitution of Glu with residues having selected side chains yields a variety of morphologies, leading to both β1- and β2-structures, that overall suggests two different packing modes for the hydrophobic side chains depending on size and type. PMID:27099990
Mechanism of Lysine 48 Selectivity during Polyubiquitin Chain Formation by the Ube2R1/2 Ubiquitin-Conjugating Enzyme.
Hill, Spencer; Harrison, Joseph S; Lewis, Steven M; Kuhlman, Brian; Kleiger, Gary
Lysine selectivity is of critical importance during polyubiquitin chain formation because the identity of the lysine controls the biological outcome. Ubiquitins are covalently linked in polyubiquitin chains through one of seven lysine residues on its surface and the C terminus of adjacent protomers. Lys 48-linked polyubiquitin chains signal for protein degradation; however, the structural basis for Lys 48 selectivity remains largely unknown. The ubiquitin-conjugating enzyme Ube2R1/2 has exquisite specificity for Lys 48, and computational docking of Ube2R1/2 and ubiquitin predicts that Lys 48 is guided to the active site through a key electrostatic interaction between Arg 54 on ubiquitin and Asp 143 on Ube2R1/2. The validity of this interaction was confirmed through biochemical experiments. Since structural examples involving Arg 54 in protein-ubiquitin complexes are exceedingly rare, these results provide additional insight into how ubiquitin-protein complexes can be stabilized. We discuss how these findings relate to how other ubiquitin-conjugating enzymes direct the lysine specificity of polyubiquitin chains. PMID:27044868
Equilibrium and surface rheology of monolayers of insoluble polycations with side chains.
Miranda, Beatriz; Hilles, Hani M; Rubio, Ramón G; Ritacco, Hernan; Radic, Deodato; Gargallo, Ligia; Sferrazza, Michele; Ortega, Francisco
We have studied monolayers of poly(n-tetradecyl 4-vinylpyridinium-co-4-vinylpyridine) bromide with different degrees of quaternization at the air-water interface. The isotherms (surface pressure vs area) present several phase transitions: at low monolayer coverage, there is a phase transition over a characteristic area that increases on increasing the quaternization degree. This behavior can be rationalized in terms of a mean-field theory of 2D semiflexible polymeric chains and could be an indication of a disorder-order transition from a 2D isotropic liquid (IL) at low surface concentration to a 2D nematic phase (N) at higher concentrations. Low-frequency oscillatory strain experiments show that at low surface coverage the monolayers exhibit highly nonlinear behavior, even for low strain amplitude, whereas at higher surface coverage the response is linear for strains higher than 20%. In addition, stress relaxation experiments show a minimum in the characteristic times that coincide with the transition area. These unexpected results at low surface coverage might be characteristic of the system or related to the fact that the oscillatory experiments do not strictly correspond to constant surface-coverage conditions. However, they are in agreement with high-frequency viscoelasticity, obtained by surface quasielastic light scattering, that shows that the dilational viscosity is higher at low surface concentration than for concentrations beyond the surface phase transition. At higher coverage, there is a second phase transition, after which the isotherms present hysteresis, which is not observed below. Ellipsometry indicates that, after this transition, the monolayer thicken, which may be related to 3D growth into a multilayer. PMID:19689139
Layered structure and Xe sorption and diffusion properties of low-density liquid-crystalline polyesters with n-alkyl side chains
NASA Astrophysics Data System (ADS)
Yoshimizu, Hiroaki; Tsukahara, Mitsuhiro; Suzuki, Tomoyuki; Toida, Jiro; Ando, Aisuke; Watanabe, Junji; Tsujita, Yoshiharu
Four low-density liquid-crystalline polyesters with n-alkyl side chains, B-C n ( n is a carbon number of n-alkyl group), were synthesized from the 1,4-di-( n-alkyl ester) of 1,2,4,5-benzenetetracarboxylic acid and 4,4'-biphenol, to clarify the effect of side chain length on higher ordered structure in the solid state and gas sorption and diffusion properties of these polyesters. All the B-C n ( n=6, 10, 14, 18) samples behaved as a thermotropic liquid crystal and formed a layered structure composed of alternating rigid aromatic main chain layers and flexible n-alkyl side chain layers. In the crystal phase, the distance between the rigid aromatic main chain layers, namely the layer spacing, linearly increased with n, indicating that the conformational feature of n-alkyl side chains was trans-rich. This finding was supported from the 13C NMR chemical shift values of methylene carbons in B-C14 and B-C18. Xe sorption of B-C n was restricted to the side chain layer, which is almost a liquid-like environment, and these sorption isotherms obeyed Henry's law. The density of side chain layers was estimated from experimental values of layer spacing and density, under some speculate assumptions, but that determined individually by 129Xe NMR spectroscopy was coincidence. The estimated density of side chain layers became higher with increasing n, as well as n-alkane liquid, and closed to that of the polyethylene in rubbery state. Xe solubility coefficient corrected with the estimated side chain layer's density decreased with increasing n. On the other hand, the diffusion coefficient of Xe in B-C n increased with n, and this was supported from the NMR spectral width of the 129Xe in B-C n. These results also indicate that the main chain layers of B-C n were very dense and could not sorb Xe.
Dielectric properties of liquid-crystal azomethine polymer with a side alkyl-substituted chain, doped with fullerene C60
NASA Astrophysics Data System (ADS)
Kovalev, D. S.; Kostromin, S. V.; Musteaţa, V.; Cozan, V.; Bronnikov, S. V.
We studied the actual and imaginary components of the dielectric constant of liquid-crystal azomethine polymer with a side chain, doped with 0.5 wt % of fullerene C60, over a wide range of temperatures and frequencies; measurements were made by means of dielectric spectroscopy. By analyzing the frequency dependence of the dielectric constant, we detected the relaxation processes (α, β1, and β2) in the nanocomposite, corresponding to certain modes of molecular motion and described them by the Arrhenius equations (β1- and β2-processes) and the Vogel-Fulcher-Tamman equation (α-process). An antiplasticization effect is discovered after doping the polymer with fullerene C60, which manifests itself in increasing the glass transition temperature of the nanocomposite compared to this parameter typical of pure polymer.
Synthesis of five and six-membered heterocycles bearing an arylpiperazinylalkyl side chain as orally active antinociceptive agents.
Vergelli, Claudia; Ciciani, Giovanna; Cilibrizzi, Agostino; Crocetti, Letizia; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Guerrini, Gabriella; Iacovone, Antonella; Giovannoni, Maria Paola
A number of heterocycles bearing an arylpiperazinylalkyl side chain and structurally related to the previously described lead ET1 (4-amino-6-methyl-2-[3-(4-p-tolylpiperazin-1-yl)propyl]-5-vinylpyridazin-3(2H)-one) was synthesized and tested for their antinociceptive activity in Writhing Test. Many compounds, tested at doses of 20-40 mg/kg po were able to reduce the number of abdominal constrictions by more than 47% and, in same cases, the potency is comparable to lead ET1 as for 5e, 24a, 27b and 27c. The analgesia induced by the active compounds was completely prevented by pretreatment with α2-antagonist yohimbine, confirming the involvement of the adrenergic system in the mechanism of action for these new compounds. PMID:26361735
In vitro and in vivo evidence for the inhibition of brassinosteroid synthesis by propiconazole through interference with side chain hydroxylation.
Oh, Keimei; Matsumoto, Tadashi; Hoshi, Tomoki; Yoshizawa, Yuko
We carried out the biochemical evaluation of the target site of propiconazole in BR biosynthesis. Applying BR biosynthesis intermediates to Arabidopsis seedlings grown in the presence of propiconazole under dark condition, we found that the target site of propiconazole in BR biosynthesis can be identified among the C22 and C23 side chain hydroxylation steps from campestanol to teasterone. Using differential spectra techniques to determine the binding affinity of propiconazole to CYP90D1, which is responsible for C23 hydroxylation of BR, we found that propiconazole induced typical type II binding spectra in response to purified recombinant CYP90D1 and the Kd value was found approximately 0.76 μM. PMID:26987039
Backbone and stereospecific (13)C methyl Ile (δ1), Leu and Val side-chain chemical shift assignments of Crc.
Sharma, Rakhi; Sahu, Bhubanananda; Ray, Malay K; Deshmukh, Mandar V
Carbon catabolite repression (CCR) allows bacteria to selectively assimilate a preferred compound among a mixture of several potential carbon sources, thus boosting growth and economizing the cost of adaptability to variable nutrients in the environment. The RNA-binding catabolite repression control (Crc) protein acts as a global post-transcriptional regulator of CCR in Pseudomonas species. Crc triggers repression by inhibiting the expression of genes involved in transport and catabolism of non-preferred substrates, thus indirectly favoring assimilation of preferred one. We report here a nearly complete backbone and stereospecific (13)C methyl side-chain chemical shift assignments of Ile (δ1), Leu and Val of Crc (~ 31 kDa) from Pseudomonas syringae Lz4W. PMID:24496608
4D APSY-HBCB(CG)CDHD experiment for automated assignment of aromatic amino acid side chains in proteins.
Krähenbühl, Barbara; Hiller, Sebastian; Wider, Gerhard
A four-dimensional (4D) APSY (automated projection spectroscopy)-HBCB(CG)CDHD experiment is presented. This 4D experiment correlates aromatic with aliphatic carbon and proton resonances from the same amino acid side chain of proteins in aqueous solution. It thus allows unambiguous sequence-specific assignment of aromatic amino acid ring signals based on backbone assignments. Compared to conventional 2D approaches, the inclusion of evolution periods on (1)H(β) and (13)C(δ) efficiently removes overlaps, and provides two additional frequencies for consequent automated or manual matching. The experiment was successfully applied to three proteins with molecular weights from 6 to 13 kDa. For the complementation of the assignment of the aromatic resonances, TOCSY- or COSY-based versions of a 4D APSY-HCCH(aro) sequence are proposed. PMID:21947871
Electrostatic Solvation Free Energy of Amino Acid Side Chain Analogs: Implications for the Validity of Electrostatic Linear Response in Water
Lin, Bin; Pettitt, Bernard M.
Electrostatic free energies of solvation for 15 neutral amino acid side chain analogs are computed. We compare three methods of varying computational complexity and accuracy for three force fields: free energy simulations, Poisson-Boltzmann (PB), and linear response approximation (LRA) using AMBER, CHARMM, and OPLSAA force fields. We find that deviations from simulation start at low charges for solutes. The approximate PB and LRA produce an overestimation of electrostatic solvation free energies for most of molecules studied here. These deviations are remarkably systematic. The variations among force fields are almost as large as the variations found among methods. Our study confirms that success of the approximate methods for electrostatic solvation free energies comes from their ability to evaluate free energy differences accurately.
Ozonolysis of surface-adsorbed methoxyphenols: kinetics of aromatic ring cleavage vs. alkene side-chain oxidation
NASA Astrophysics Data System (ADS)
O'Neill, E. M.; Kawam, A. Z.; Van Ry, D. A.; Hinrichs, R. Z.
Lignin pyrolysis products, which include a variety of substituted methoxyphenols, constitute a major component of organics released by biomass combustion, and may play a central role in the formation of atmospheric brown carbon. Understanding the atmospheric fate of these compounds upon exposure to trace gases is therefore critical to predicting the chemical and physical properties of biomass burning aerosol. We used diffuse reflectance infrared spectroscopy to monitor the heterogeneous ozonolysis of 4-propylguaiacol, eugenol, and isoeugenol adsorbed on NaCl and α-Al2O3 substrates. Adsorption of gaseous methoxyphenols onto these substrates produced near-monolayer surface concentrations of 3 × 1018 molecules m-2. The subsequent dark heterogeneous ozonolysis of adsorbed 4-propylguaiacol cleaved the aromatic ring between the methoxy and phenol groups with the product conclusively identified by GC-MS and 1H-NMR. Kinetic analysis of eugenol and isoeugenol dark ozonolysis also suggested the formation of ring-cleaved products, although ozonolysis of the unsaturated substituent groups forming carboxylic acids and aldehydes was an order of magnitude faster. Average uptake coefficients for NaCl-adsorbed methoxyphenols were γ = 2.3 (± 0.8) × 10-7 and 2 (± 1) × 10-6 for ozonolysis of the aromatic ring and the unsaturated side chain, respectively, and reactions on α-Al2O3 were approximately two times slower. UV-visible radiation (λ > 300 nm) enhanced eugenol ozonolysis of the aromatic ring by a factor of 4(± 1) but had no effect on ozonolysis of the alkene side chain.
Dynamic properties of the native free antithrombin from molecular dynamics simulations: computational evidence for solvent- exposed Arg393 side chain.
Tóth, László; Fekete, Attila; Balogh, Gábor; Bereczky, Zsuzsanna; Komáromi, István
While antithrombin (AT) has small basal inhibitory activity, it reaches its full inhibitory potential against activated blood coagulation factors, FXa, FIXa, and FIIa (thrombin), via an allosteric and/or template (bridging) mechanism by the action of heparin, heparan sulfate, or heparin-mimetic pentasaccharides (PS). From the numerous X-ray structures available for different conformational states of AT, only indirect and incomplete conclusions can be drawn on the inherently dynamic properties of AT. As a typical example, the basal inhibitory activity of AT cannot be interpreted on the basis of "non-activated" free antithrombin X-ray structures since the Arg393 side chain, playing crucial role in antithrombin-proteinase interaction, is not exposed. In order to reveal the intrinsic dynamic properties and the reason of basal inhibitory activity of antithrombin, 2 μs molecular dynamics simulations were carried out on its native free-forms. It was shown from the simulation trajectories that the reactive center loop which is functioning as "bait" for proteases, even without any biasing potential can populate conformational state in which the Arg393 side chain is solvent exposed. It is revealed from the trajectory analysis that the peptide sequences correspond to the helix D extension, and new helix P formation can be featured with especially large root-mean-square fluctuations. Mutual information analyses of the trajectory showed remarkable (generalized) correlation between those regions of antithrombin which changed their conformations as the consequence of AT-PS complex formation. This suggests that allosteric information propagation pathways are present even in the non-activated native form of AT. PMID:25483839
Amide side chain amphiphilic polymers disrupt surface established bacterial bio-films and protect mice from chronic Acinetobacter baumannii infection.
Uppu, Divakara S S M; Samaddar, Sandip; Ghosh, Chandradhish; Paramanandham, Krishnamoorthy; Shome, Bibek R; Haldar, Jayanta
Bacterial biofilms represent the root-cause of chronic or persistent infections in humans. Gram-negative bacterial infections due to nosocomial and opportunistic pathogens such as Acinetobacter baumannii are more difficult to treat because of their inherent and rapidly acquiring resistance to antibiotics. Due to biofilm formation, A. baumannii has been noted for its apparent ability to survive on artificial surfaces for an extended period of time, therefore allowing it to persist in the hospital environment. Here we report, maleic anhydride based novel cationic polymers appended with amide side chains that disrupt surface established multi-drug resistant A. baumannii biofilms. More importantly, these polymers significantly (p < 0.0001) decrease the bacterial burden in mice with chronic A. baumannii burn wound infection. The polymers also show potent antibacterial efficacy against methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococci (VRE) and multi-drug resistant clinical isolates of A. baumannii with minimal toxicity to mammalian cells. We observe that optimal hydrophobicity dependent on the side chain chemical structure of these polymers dictate the selective toxicity to bacteria. Polymers interact with the bacterial cell membranes by causing membrane depolarization, permeabilization and energy depletion. Bacteria develop rapid resistance to erythromycin and colistin whereas no detectable development of resistance occurs against these polymers even after several passages. These results suggest the potential use of these polymeric biomaterials in disinfecting biomedical device surfaces after the infection has become established and also for the topical treatment of chronic bacterial infections. PMID:26454051
Involvement of a cytosine side chain in proton transfer in the rate-determining step of ribozyme self-cleavage.
Shih, I H; Been, M D
Ribozymes of hepatitis delta virus have been proposed to use an active-site cytosine as an acid-base catalyst in the self-cleavage reaction. In this study, we have examined the role of cytosine in more detail with the antigenomic ribozyme. Evidence that proton transfer in the rate-determining step involved cytosine 76 (C76) was obtained from examining cleavage activity of the wild-type and imidazole buffer-rescued C76-deleted (C76 Delta) ribozymes in D(2)O and H(2)O. In both reactions, a similar kinetic isotope effect and shift in the apparent pKa indicate that the buffer is functionally substituting for the side chain in proton transfer. Proton inventory of the wild-type reaction supported a mechanism of a single proton transfer at the transition state. This proton transfer step was further characterized by exogenous base rescue of a C76 Delta mutant with cytosine and imidazole analogues. For the imidazole analogues that rescued activity, the apparent pKa of the rescue reaction, measured under k(cat)/K(M) conditions, correlated with the pKa of the base. From these data a Brønsted coefficient (beta) of 0.51 was determined for the base-rescued reaction of C76 Delta. This value is consistent with that expected for proton transfer in the transition state. Together, these data provide strong support for a mechanism where an RNA side chain participates directly in general acid or general base catalysis of the wild-type ribozyme to facilitate RNA cleavage. PMID:11171978
Periodic variation in side-chain polarities of T-cell antigenic peptides correlates with their structure and activity.
Cornette, J L; Margalit, H; Berzofsky, J A; DeLisi, C
We present an analysis that synthesizes information on the sequence, structure, and motifs of antigenic peptides, which previously appeared to be in conflict. Fourier analysis of T-cell antigenic peptides indicates a periodic variation in amino acid polarities of 3-3.6 residues per period, suggesting an amphipathic alpha-helical structure. However, the diffraction patterns of major histocompatibility complex (MHC) molecules indicate that their ligands are in an extended non-alpha-helical conformation. We present two mutually consistent structural explanations for the source of the alpha-helical periodicity, based on an observation that the side chains of MHC-bound peptides generally partition with hydrophobic (hydrophilic) side chains pointing into (out of) the cleft. First, an analysis of haplotype-dependent peptide motifs indicates that the locations of their defining residues tend to force a period 3-4 variation in hydrophobicity along the peptide sequence, in a manner consistent with the spacing of pockets in the MHC. Second, recent crystallographic determination of the structure of a peptide bound to a class II MHC molecule reveals an extended but regularly twisted peptide with a rotation angle of about 130 degrees. We show that similar structures with rotation angles of 100-130 degrees are energetically acceptable and also span the length of the MHC cleft. These results provide a sound physical chemical and structural basis for the existence of a haplotype-independent antigenic motif which can be particularly important in limiting the search time for antigenic peptides. Images Fig. 3 PMID:7667297
Self-organizing conjugated polymers
NASA Astrophysics Data System (ADS)
Hong, Xiaoyong Michael
A general and efficient synthetic route to semifluoroalkyl substituted thiophenes has been developed and a series of 3-semifluoroalkylthiophenes were synthesized. The lengths of the fluorocarbon chain and hydrocarbon spacer between thiophene and fluorocarbon were systematically altered to study their effect on the properties of the resulting polymers. Oxidative polymerization (FeCl3) and electrochemical polymerization of 3-semifluoroalkylthiophenes afforded regiorandom (head-to-tail coupling ˜70%) homopolymers. The solubility and thermal transition temperatures of the polymers are also dependent on the nature of side chains. The surface properties of the polymers are also a function of the length of fluoroalkyl side chains. From x-ray diffraction, the regiorandom polymers have low crystallinity. Two synthetic methods have been successfully utilized to prepare regioregular poly(3-semifluoroalkylthiophene)s (head-to-tail coupling >90%) and gave identical polymers. The regioregular polymers are highly conjugated and highly ordered. The long side chain substituted polythiophenes form a liquid crystal mesophase between the crystal solid and isotropic liquid phases. To prepare polymers bearing alternating 3-semifluoroalkylthiophene and alkylthiophene units, we developed synthetic methods to 3-semifluoroalkyl-4 '-alkyl-2,2'-bithiophenes. The 3-semifluoroalkyl-4 '-alkyl-2,2'-bithiophenes were polymerized to afford regiorandom and regioregular polymers. Regiorandom polymers have low crystallinity and conjugation. Regioregular, strictly alternating copolymer with 3-semifluoroalkylthiophene and alkylthiophene units are highly conjugated and ordered. The regioregular polymers self-assemble into bilayer structure in solid state due to phase separation between fluorocarbon and hydrocarbon. At high temperatures close to melting transition, the thiophene rings rotate and twist along the molecular axis to give a single layer structure. Methylene bridges were placed between the
Dependence of Excited-State Properties of a Low-Bandgap Photovoltaic Copolymer on Side-Chain Substitution and Solvent.
Zhao, Ning-Jiu; Zhang, Mao-Jie; Liang, Ran; Fu, Li-Min; Zhang, Wei; Ai, Xi-Cheng; Hou, Jian-Hui; Zhang, Jian-Ping
The excited-state properties and chain conformations of a new low-bandgap copolymer based on benzo[1,2-b:4,5-b']dithiophene (BDT) and thieno[3,4-b]thiophene with meta-alkoxyphenyl-substituted side chains in solution were investigated comprehensively. Time-resolved spectroscopy suggested that the excited-state properties were sensitive to the conformations of the copolymer in solution. In addition, excited-state dynamics analyses revealed the photogeneration of triplet excited states by intersystem crossing (ISC) at a rate constant of ∼0.4×10(9) s(-1) as a result of direct meta-alkoxyphenyl connection to the donor unit BDT irrespective to the macromolecular conformations. According to El-Sayed's rule, the fast ISC herein is correlated with the change of orbital types between singlet and triplet excited states as also shown by quantum chemical calculations. Our studies may shed light on the structure-property relationships of photovoltaic materials. PMID:27226175
Accordion-like oscillation of contracted and stretched helices of polyacetylenes synchronized with the restricted rotation of side chains.
Yoshida, Yoshiaki; Mawatari, Yasuteru; Motoshige, Asahi; Motoshige, Ranko; Hiraoki, Toshifumi; Wagner, Manfred; Müllen, Klaus; Tabata, Masayoshi
A chiral substituted acetylene, (s)-2-octyl propiolate, was stereoregularly polymerized using a catalyst, [Rh(nbd)Cl]2, at 40 °C in methanol to give the corresponding helical polymer, Ps2OcP. The changes of (1)H and (13)C NMR spectra in line shapes and splitting patterns were consistently interpreted in terms of restricted rotation around the ester O-*C bond, ~O-*C(ε)H(ε)(R)~, R = a branched CH(ε)3 in the ester side chains rather than the helix inversion with the aid of a 3-site jump model. Three peaks due to the branched methyl H(ε) proton and its C(η) carbon observed at 0 °C suggested the formation of three rotamers called A, B, and C, based on the presence of the contracted helix and stretched helix forms that have an intrinsic helical pitch. Furthermore, an accordion-like helix oscillation (HELIOS) along the main chain axis was proposed to explain the temperature dependence spectral changes observed in (1)H and (13)C NMR, UV-vis, and circular dicromism (CD) spectra. The temperature dependence UV-vis and CD spectra of Ps2OcP corroborate the presence of contracted and stretched one-handed helix sense polymers in solution in which the helical pitches and their persistence lengths depend on the temperature. PMID:23402213
Development of a sufficiently reactive thioalkylester involving the side-chain thiol of cysteine applicable for kinetically controlled ligation.
Tsuda, Shugo; Mochizuki, Masayoshi; Nishio, Hideki; Yoshiya, Taku; Nishiuchi, Yuji
N(α) -Trifluoroacetyl-Cys-Leu-NH2 (TfaC-Leu-NH2 ) was incorporated into thioesters through its side-chain thiol group to develop a more reactive peptide-thioester than the commonly used peptide-3-mercaptopropionic acid (MPA)-thioester. The TfaC-thioester could be readily synthesized by solid-phase peptide synthesis (SPPS) with Boc chemistry using in situ neutralization protocols in sufficient yield without any side reaction associated with the use of TfaC. This thioester proved to display a much higher reactivity in the thiol-free native chemical ligation (NCL) reaction than the MPA-thioester and to be comparable to the thioarylester, such as the 4-mercaptophenylacetic acid (MPAA)-thioester, in terms of the ligation rate. We were able to demonstrate the usefulness of the TfaC-thioester by using it to synthesize neuromedin S via a one-pot sequential NCL approach followed by desulfurization. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 503-511, 2016. PMID:26583564
The effect of side-chain functionality and hydrophobicity on the gene delivery capabilities of cationic helical polypeptides.
Zhang, Rujing; Zheng, Nan; Song, Ziyuan; Yin, Lichen; Cheng, Jianjun
The rational design of effective and safe non-viral gene vectors is largely dependent on the understanding of the structure-property relationship. We herein report the design of a new series of cationic, α-helical polypeptides with different side charged groups (amine and guanidine) and hydrophobicity, and mechanistically unraveled the effect of polypeptide structure on the gene delivery capability. Guanidine-containing polypeptides displayed superior membrane activities to their amine-containing analogues via the pore formation mechanism, and thus possessed notably higher transfection efficiencies. Elongating the hydrophobic side chain also potentiated the membrane activities of the polypeptides, while at the meantime caused higher cytotoxicities. Upon an optimal balance between membrane activity and cytotoxicity, maximal transfection efficiency was achieved which outperformed commercial reagent Lipofectamine™ 2000 (LPF2000) by 3-6 folds. This study thus provides mechanistic insights into the rational design of non-viral gene delivery vectors, and the best-performing materials identified also serve as a promising addition to the existing systems. PMID:24439403
High-definition NMR structure of PED/PEA-15 death effector domain reveals details of key polar side chain interactions.
Twomey, Edward C; Wei, Yufeng
Death effector domain (DED) proteins constitute a subfamily of the large death domain superfamily that is primarily involved in apoptosis pathways. DED structures have characteristic side chain-side chain interactions among polar residues on the protein surface, forming a network of hydrogen bonds and salt bridges. The polar interaction network is functionally important in promoting protein-protein interactions by maintaining optimal side chain orientations. We have refined the solution DED structure of the PED/PEA-15 protein, a representative member of DED subfamily, using traditional NMR restraints with the addition of residual dipolar coupling (RDC) restraints from two independent alignment media, and employed the explicit solvent refinement protocol. The newly refined DED structure of PED/PEA-15 possesses higher structural quality as indicated by WHAT IF Z-scores, with most significant improvement in the backbone conformation normality quality factor. This higher quality DED structure of PED/PEA-15 leads to the identification of a number of key polar side chain interactions, which are not typically observed in NMR protein structures. The elucidation of polar side chain interactions is a key step towards the understanding of protein-protein interactions involving the death domain superfamily. The NMR structures with extensive details of protein structural features are thereby termed high-definition (HD) NMR structures. PMID:22732408
Exploiting Supramolecular Interactions for the Intramolecular Folding of Side-Chain Functionalized Polymers and Assembly of Anisotropic Colloids
NASA Astrophysics Data System (ADS)
Romulus, Joy
The overarching goal presented in this thesis is the self-assembly of synthetic systems into higher ordered structures utilizing supramolecular chemistry. Noncovalent interactions including charge-transfer and hydrogen bonding as well as DNA hybridization are exploited to induce the assembly of polymers and colloids into well-defined architectures. This strategy provides a tunable handle on materials bulk properties that can be adjusted by simply changing variables such as temperature and solvent. A brief overview of design principles for the supramolecular assembly of side-chain functionalized polymers is presented. The polymerization technique selected was living ring-opening metathesis polymerization (ROMP), thus affording control over molecular weight and molecular weight distributions. ROMP also allowed for the incorporation of functional groups that were used to assemble the polymers into ordered structures. Charge-transfer motifs were exploited and shown to drive the assembly of random and alternating copolymers via intramolecular side-chain interactions. Incorporation of complementary hydrogen bonding motifs was shown to guide the single-chain folding of a multifunctional triblock copolymer into sheet-like structures. Precision over the size, shape, and monomer sequence were identified as key elements for efficient self-assembly. The self-assembly of colloids using DNA hybridization was also investigated. Previously, the majority of colloid-based research relied upon the self-assembly of spherical isotropic particles into closed-packed arrangements. In contrast, anisotropic particles may allow for the realization of open structures. By expanding upon a method to permanently cross-link DNA strands incubated on a colloidal surface, a new strategy to engineer patchy particles is described. These functional DNA-coated patches are demonstrated to direct particle assembly. The self-assembly of polymer and colloidal systems utilizing noncovalent interactions
Quantum transport through a multi-quantum-dot-pair chain side-coupled with Majorana bound states
NASA Astrophysics Data System (ADS)
Zhao-Tan, Jiang; Cheng-Cheng, Zhong
We investigate the quantum transport properties through a special kind of quantum dot (QD) system composed of a serially coupled multi-QD-pair (multi-QDP) chain and side-coupled Majorana bound states (MBSs) by using the Green functions method, where the conductance can be classified into two kinds: the electron tunneling (ET) conductance and the Andreev reflection (AR) one. First we find that for the nonzero MBS-QDP coupling a sharp AR-induced zero-bias conductance peak with the height of e 2/h is present (or absent) when the MBS is coupled to the far left (or the other) QDP. Moreover, the MBS-QDP coupling can suppress the ET conductance and strengthen the AR one, and further split into two sub-peaks each of the total conductance peaks of the isolated multi-QDPs, indicating that the MBS will make obvious influences on the competition between the ET and AR processes. Then we find that the tunneling rate Γ L is able to affect the conductances of leads L and R in different ways, demonstrating that there exists a Γ L-related competition between the AR and ET processes. Finally we consider the effect of the inter-MBS coupling on the conductances of the multi-QDP chains and it is shown that the inter-MBS coupling will split the zero-bias conductance peak with the height of e 2/h into two sub-peaks. As the inter-MBS coupling becomes stronger, the two sub-peaks are pushed away from each other and simultaneously become lower, which is opposite to that of the single QDP chain where the two sub-peaks with the height of about e 2/2h become higher. Also, the decay of the conductance sub-peaks with the increase of the MBS-QDP coupling becomes slower as the number of the QDPs becomes larger. This research should be an important extension in studying the transport properties in the kind of QD systems coupled with the side MBSs, which is helpful for understanding the nature of the MBSs, as well as the MBS-related QD transport properties. Project supported by the National Natural
Chi(1) rotamer populations and angles of mobile surface side chains are accurately predicted by a torsion angle database potential of mean force.
Clore, G Marius; Kuszewski, John
The equilibrium angles and distributions of chi(1) rotamers for mobile surface side chains of the small, 63-residue, B1 domain of protein L have been calculated from the static crystal structure by rigid body/torsion angle simulated annealing using a torsion angle database potential of mean force and compared to those deduced by Monte Carlo analysis of side chain residual dipolar couplings measured in solution. Good agreement between theory and experiment is observed, indicating that for side chains undergoing rotamer averaging that is fast on the chemical shift time scale, the equilibrium angles and distribution of chi(1) rotamers are largely determined by the backbone phi/psi torsion angles. PMID:11902865
Liquid crystal alignment on ion-beam-treated polyimide with a long alkyl side chain: near edge X-ray absorption fine structure spectroscopy analysis.
Seo, Joo-Hong; Hwang, Soo Won; Song, Dong Han; Shin, Jae Hoon; Yoon, Tae-Hoon; Kim, Jae Chang; Yi, Mi Hye
Liquid crystal alignment on ion-beam-treated polyimides with a long alkyl side chain was investigated using near edge X-ray absorption fine structure (NEXAFS) spectroscopy. The long alkyl side chains and the asymmetric distribution and orientational order of the pi-bonds of the polyimide surface can be determined by analyzing the angular dependent resonance intensities of the NEXAFS measurements. Herein, we demonstrate that the pretilt angle of the LC cell made by our method decreases as more long alkyl side chains are destroyed. Additionally, the tilt direction of the LC molecules can be determined from the asymmetric distribution of pi-bonds of the polyimide created by the ion beam irradiation. PMID:19161281
The role of side chain entropy and mutual information for improving the de novo design of Kemp eliminases KE07 and KE70.
Bhowmick, Asmit; Sharma, Sudhir C; Honma, Hallie; Head-Gordon, Teresa
Side chain entropy and mutual entropy information between residue pairs have been calculated for two de novo designed Kemp eliminase enzymes, KE07 and KE70, and for their most improved versions at the end of laboratory directed evolution (LDE). We find that entropy, not just enthalpy, helped to destabilize the preference for the reactant state complex of the designed enzyme as well as favoring stabilization of the transition state complex for the best LDE enzymes. Furthermore, residues with the highest side chain couplings as measured by mutual information, when experimentally mutated, were found to diminish or annihilate catalytic activity, some of which were far from the active site. In summary, our findings demonstrate how side chain fluctuations and their coupling can be an important design feature for de novo enzymes, and furthermore could be utilized in the computational steps in lieu of or in addition to the LDE steps in future enzyme design projects. PMID:27374812
Coupling between side chain interactions and binding pocket flexibility in HLA-B*44:02 molecules investigated by molecular dynamics simulations.
Ostermeir, Katja; Springer, Sebastian; Zacharias, Martin
MHC class I molecules present antigenic peptides to cytotoxic T-cells at the cell surface. Peptide loading of class I molecules in the endoplasmatic reticulum can involve interaction with the tapasin chaperone protein. The human class I allotype HLA-B*44:02 with an Asp at position 116 at the floor of the F pocket (which binds the peptide C-terminal residues) depends on tapasin for efficient peptide loading. However, HLA-B*44:05 (identical to B*44:02 except for tyrosine 116) can efficiently load peptides in the absence of tapasin. Both allotypes adopt very similar structures in the presence of the same peptide. Molecular dynamics simulations indicate a significantly higher conformational flexibility of the F pocket in the absence of a peptide for B*44:02 compared to B*44:05. Free energy simulations to open the F pocket indicate a molecular side chain switch mechanism that underlies the global opening motion. This side chain switch involves the rearrangement of salt bridges and hydrogen bonding of the basic arginine 97 with three acidic aspartate residues 114, 116 and 156 near the F pocket. A replica exchange simulation to specifically accelerate side chain motions demonstrates that the same side chain rearrangements induce global opening motions of the F pocket. In case of B*44:05 the free energy barrier for F pocket opening was significantly higher compared to B*44:02 and no associated side chain rearrangement was observed. Such coupling of local side chain rearrangements with global conformational changes might be the basis for allosteric changes in other class I allotypes as well as for allosteric changes in other proteins. PMID:25146482
The effects of side-chain-induced disorder on the emission spectra and quantum yields of oligothiophene nano-aggregates. A combined experimental and MD-TDDFT study
Hong, Jiyun; Jeon, SuKyung; Kim, Janice J.; Devi, Diane; Chacon-Madrid, Kelly; Lee, Wynee; Koo, Seung Moh; Wildeman, Jurjen; Sfeir, Matthew Y.; Peteanu, Linda A.; Wen, Jin; Ma, Jing
Oligomeric thiophenes are commonly-used components in organic electronics and solar cells. These molecules stack and/or aggregate readily under the processing conditions used to form thin films for these applications, significantly altering their optical and charge-transport properties. To determine how these effects depend on the substitution pattern of the thiophene main chains, nano-aggregates of three sexi-thiophene (6T) oligomers having different alkyl substitution patterns were formed using solvent poisoning techniques and studied using steady-state and time-resolved emission spectroscopy. The results indicate the substantial role played by the side-chain substituents in determining the emissive properties of these species. Both the measured spectral changes and their dependence on substitution are well modeled by combined quantum chemistry and molecular dynamics simulations. The simulations connect the side-chain-induced disorder, which determines the favorable chain packing configurations within the aggregates, with their measured electronic spectra.
C35 Hopanoid Side Chain Biosynthesis: Reduction of Ribosylhopane into Bacteriohopanetetrol by a Cell-Free System Derived from Methylobacterium organophilum.
Bodlenner, Anne; Liu, Wenjun; Hirsch, Guillaume; Schaeffer, Philippe; Blumenberg, Martin; Lendt, Ralf; Tritsch, Denis; Michaelis, Walter; Rohmer, Michel
The major bacterial triterpenoids of the hopane series each consist of a C30 triterpene hopane moiety and an additional nonterpene C5 side chain derived from D-ribose and linked through its C-5 carbon atom to the hopane side chain. Bacteriohopanetetrol and aminobacteriohopanetriol are the most common representatives of this natural product series, adenosylhopane and ribosylhopane being putative precursors. Deuterium-labelled ribosylhopane was obtained by hemisynthesis and converted into deuterium-labelled bacteriohopanetetrol in the presence of NADPH, thus giving evidence of this as yet unknown precursor-to-product relationship in the bacterial hopanoid metabolic pathway. PMID:26032177
Using infrared spectroscopy of a nitrile labeled phenylalanine and tryptophan fluorescence to probe the α-MSH peptide's side-chain interactions with a micelle model membrane
NASA Astrophysics Data System (ADS)
Gonzalez, Javier D.; Levonyak, Nicholas S.; Schneider, Sydney C.; Smith, Matthew J.; Cremeens, Matthew E.
The interactions of α-MSH (Ac-SYSMEHFRWGKPV-NH2) side-chains were biophysically characterized with a micelle model membrane and in model intracellular bacterial conditions using infrared (IR) spectroscopy of a nitrile labeled α-MSH analogue, circular dichroism (CD), and tryptophan fluorescence. Local changes detected by the tryptophan and a nitrile-labeled phenylalanine using fluorescence and infrared spectroscopies, respectively, suggest that the Trp9 side-chain in the conserved core (HisPheArgTrp) of α-MSH is buried in an SDS micellar environment, while Phe(CN)7 does not appear to be buried.
Supramolecular side-chain poly[2]pseudorotaxanes formed by orthogonal coordination-driven self-assembly and crown-ether-based host-guest interactions.
Xing, Hao; Wei, Peifa; Yan, Xuzhou
The themes of coordination-driven self-assembly, host-guest interactions, and supramolecular polymerization are unified in an orthogonal noninterfering fashion to deliver side-chain poly[2]pseudorotaxanes. Specifically, a bis(p-phenylene)-34-crown-10 derivative 1 bearing two pyridyl groups polymerizes into a side-chain poly[2]pseudorotaxane upon the addition of di-Pt(II) acceptor 4 in the presence of paraquat. Interestingly, by adding a competitive guest 3, the poly[2]pseudorotaxane can realize a conversion in one pot. PMID:24819441
Removal of the side-chain glucose groups from schizophyllan improves the thermal stability of the polycytidylic acid complexes under the physiological conditions.
Koumoto, Kazuya; Karinaga, Ryouji; Mizu, Masami; Anada, Takahisa; Sakurai, Kazuo; Kunitake, Toyoki; Shinkai, Seiji
Thermal stabilization of the complex between polycytidylic acid [poly(C)] and the modified schizophyllan (SPG) whose hydrophilic side-chain glucose groups are selectively removed utilizing mild Smith-degradation has been investigated. With the decrease in the side-chain glucose groups of schizophyllan, the complex with poly(C) can be considerably stabilized compared with unmodified SPG; for example, the T(m) value after the removal of the side-chain glucose groups from 33.3 (unmodified) to 1.0 is enhanced by 14 degrees C. In addition, the thermal stabilization effect is even operative under the physiological conditions ([NaCl] = 0.15 mol dm(-3)). This effect is exerted owing to the construction of the hydrophobic atmosphere around the complex. Although schizophyllan lost the side-chain glucose groups, it still kept the protection effect of the bound poly(C) chain against RNaseA-mediated hydrolysis as observed for unmodified schizophyllan. The assessment of the cytotoxicity for A375:human malignant melanoma, and HL60:human promyelocytic leukemia revealed that the modified schizophyllan scarcely increases the cytotoxicity. These results indicate that the present modification for schizophyllan is of great significance in a viewpoint to develop the practical gene carriers operative even under the physiological conditions. PMID:15457435
Synthesis, structure and antimicrobial evaluation of a new gossypol triazole conjugates functionalized with aliphatic chains and benzyloxy groups.
Pyta, Krystian; Blecha, Marietta; Janas, Anna; Klich, Katarzyna; Pecyna, Paulina; Gajecka, Marzena; Przybylski, Piotr
Synthetic limitations in the copper-catalyzed azide alkyne cycloaddition (CuAAC) on gossypol's skeleton functionalized with alkyne (2) or azide (3) groups have been indicated. Modified approach to the synthesis of new gossypol-triazole conjugates yielded new compounds (24-31) being potential fungicides. Spectroscopic studies of triazole conjugates 24-31 have revealed their structures in solution, i.e., the presence of enamine-enamine tautomeric forms and π-π stacking intramolecular interactions between triazole arms. Biological evaluation of the new gossypol-triazole conjugates revealed the potency of 30 and 31 derivatives, having triazole-benzyloxy moieties, comparable with that of miconazole against Fusarium oxysporum. The results of HPLC evaluation of ergosterol content in different fungi strains upon treatment of gossypol and its derivatives enabled to propose a mechanism of antifungal activity of these compounds. PMID:27469129
Main-Chain and Side-Chain Sequence-Regulated Vinyl Copolymers by Iterative Atom Transfer Radical Additions and 1:1 or 2:1 Alternating Radical Copolymerization.
Soejima, Takamasa; Satoh, Kotaro; Kamigaito, Masami
Main- and side-chain sequence-regulated vinyl copolymers were prepared by a combination of iterative atom transfer radical additions (ATRAs) of vinyl monomers for side-chain control and 1:1 or 2:1 alternating radical copolymerization of the obtained side-chain sequenced "oligomonomers" and vinyl comonomers for main-chain control. A complete set of sequence-regulated trimeric vinyl oligomers of styrene (S) and/or methyl acrylate (A) were first synthesized via iterative ATRAs of these monomers to a halide of monomeric S or A unit (X-S or X-A) under optimized conditions with appropriate ruthenium or copper catalysts, which were selected depending on the monomers and halides. The obtained halogen-capped oligomers were then converted into a series of maleimide (M)-ended oligomonomers with different monomer compositions and sequences (M-SSS, M-ASS, M-SAS, M-AAS, M-SSA, M-ASA, M-SAA, M-AAA) by a substitution reaction of the halide with furan-protected maleimide anion followed by deprotection of the furan units. These maleimide-ended oligomonomers were then radically copolymerized with styrene or limonene to enable the 1:1 or 2:1 monomer-sequence regulation in the main chain and finally result in the main- and side-chain sequence-regulated vinyl copolymers with high molecular weights in high yield. The properties of the sequence-regulated vinyl copolymers depended on not only the monomer compositions but also the monomer sequences. The solubility was highly affected by the outer monomer units in the side chains whereas the glass transition temperatures were primarily affected by the two successive monomer sequences. PMID:26761148
Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury.
Gotha, Lara; Lim, Sang Yup; Osherov, Azriel B; Wolff, Rafael; Qiang, Beiping; Erlich, Ilana; Nili, Nafiseh; Pillarisetti, Sivaram; Chang, Ya-Ting; Tran, Phan-Kiet; Tryggvason, Karl; Hedin, Ulf; Tran-Lundmark, Karin; Advani, Suzanne L; Gilbert, Richard E; Strauss, Bradley H
Perlecan is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2(Δ3/Δ3) (MΔ3/Δ3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from MΔ3/Δ3 and wild-type mice. Proliferation of MΔ3/Δ3 SMC was 1.5× greater than in wild type (P < 0.001), increased by addition of growth factors, and showed a 42% greater migratory response than wild-type cells to PDGF-BB (P < 0.001). In MΔ3/Δ3 SMC adhesion to fibronectin, and collagen types I and IV was significantly greater than wild type. Addition of DRL-12582, an inducer of perlecan expression, decreased proliferation and migratory response to PDGF-BB stimulation in wild-type SMC compared with MΔ3/Δ3. In an in vivo carotid artery wire injury model, the medial thickness, medial area/lumen ratio, and macrophage infiltration were significantly increased in the MΔ3/Δ3 mice, indicating a prominent role of the HS side chain in limiting vascular injury response. Mutant perlecan that lacks HS side chains had a marked reduction in the inhibition of in vitro SMC function and the in vivo arterial response to injury, indicating the critical role of HS side chains in perlecan function in the vessel wall. PMID:24858854
An effective strategy to increase hydroxide-ion conductivity through microphase separation induced by hydrophobic-side chains
NASA Astrophysics Data System (ADS)
Zeng, L.; Zhao, T. S.
A highly conductive and durable anion exchange membrane (AEM) is an essential component for alkaline electrochemical conversion and storage systems. Contrary to the conventional wisdom that the ionic conductivity can be improved by increasing the ion exchange capacity (IEC) through a cross-linking process, in this work, a new approach to improve the ionic conductivity by enhancing the ionic mobility is adopted. The microstructure of quaternary ammonia poly (2, 6-dimethyl-1, 4-phenylene oxide) (QAPPO) is manipulated through grafting with hydrophobic side chains, which will drive the well-established hydrophilic/hydrophobic domains and nano-phase separated, well-connected ionic channels. As a result, the local hydroxide concentration is enhanced by the novel microstructure, thereby improving the ionic conductivity of the as-prepared ionomers. The as-prepared ionomers, denoted as self-aggregated QAPPO-CF, with an intermediate IEC value achieved an ionic conductivity of 65 mS cm-1 at 80 °C, outperforming the QAPPO with an even higher IEC value. This result suggests that the microphase separation is an effective approach to enhance the ionic conductivity.
Improving physical realism, stereochemistry and side-chain accuracy in homology modeling: four approaches that performed well in CASP8
Krieger, Elmar; Joo, Keehyoung; Lee, Jinwoo; Lee, Jooyoung; Raman, Srivatsan; Thompson, James; Tyka, Mike; Baker, David; Karplus, Kevin
A correct alignment is an essential requirement in homology modeling. Yet in order to bridge the structural gap between template and target, which may not only involve loop rearrangements, but also shifts of secondary structure elements and repacking of core residues, high-resolution refinement methods with full atomic details are needed. Here we describe four approaches that address this 'last mile of the protein folding problem' and have performed well during CASP8, yielding physically realistic models: YASARA, which runs molecular dynamics simulations of models in explicit solvent, using a new partly knowledge-based all atom force field derived from Amber, whose parameters have been optimized to minimize the damage done to protein crystal structures. The LEE-SERVER, which makes extensive use of conformational space annealing to create alignments, to help Modeller build physically realistic models while satisfying input restraints from templates and CHARMM stereochemistry, and to remodel the side-chains. ROSETTA, whose high resolution refinement protocol combines a physically realistic all atom force field with Monte Carlo minimization to allow the large conformational space to be sampled quickly. And finally UNDERTAKER, which creates a pool of candidate models from various templates and then optimizes them with an adaptive genetic algorithm, using a primarily empirical cost function that does not include bond angle, bond length, or other physics-like terms. PMID:19768677
Side-chain control of porosity closure in single- and multiple-peptide-based porous materials by cooperative folding
NASA Astrophysics Data System (ADS)
Martí-Gastaldo, C.; Antypov, D.; Warren, J. E.; Briggs, M. E.; Chater, P. A.; Wiper, P. V.; Miller, G. J.; Khimyak, Y. Z.; Darling, G. R.; Berry, N. G.; Rosseinsky, M. J.
Porous materials are attractive for separation and catalysis—these applications rely on selective interactions between host materials and guests. In metal-organic frameworks (MOFs), these interactions can be controlled through a flexible structural response to the presence of guests. Here we report a MOF that consists of glycyl-serine dipeptides coordinated to metal centres, and has a structure that evolves from a solvated porous state to a desolvated non-porous state as a result of ordered cooperative, displacive and conformational changes of the peptide. This behaviour is driven by hydrogen bonding that involves the side-chain hydroxyl groups of the serine. A similar cooperative closure (reminiscent of the folding of proteins) is also displayed with multipeptide solid solutions. For these, the combination of different sequences of amino acids controls the framework's response to the presence of guests in a nonlinear way. This functional control can be compared to the effect of single-point mutations in proteins, in which exchange of single amino acids can radically alter structure and function.
Fluorinated Peptide Nucleic Acids with Fluoroacetyl Side Chain Bearing 5-(F/CF3)-Uracil: Synthesis and Cell Uptake Studies.
Ellipilli, Satheesh; Palvai, Sandeep; Ganesh, Krishna N
Fluorine incorporation into organic molecules imparts favorable physicochemical properties such as lipophilicity, solubility and metabolic stability necessary for drug action. Toward such applications using peptide nucleic acids (PNA), we herein report the chemical synthesis of fluorinated PNA monomers and biophysical studies of derived PNA oligomers containing fluorine in in the acetyl side chain (-CHF-CO-) bearing nucleobase uracil (5-F/5-CF3-U). The crystal structures of fluorinated racemic PNA monomers reveal interesting base pairing of enantiomers and packing arrangements directed by the chiral F substituent. Reverse phase HPLC show higher hydrophobicity of fluorinated PNA oligomers, dependent on the number and site of the fluorine substitution: fluorine on carbon adjacent to the carbonyl group induces higher lipophilicity than fluorine on nucleobase or in the backbone. The PNA oligomers containing fluorinated bases form hybrids with cDNA/RNA with slightly lower stability compared to that of unmodified aeg PNA, perhaps due to electronic effects. The uptake of fluorinated homooligomeric PNAs by HeLa cells was as facile as that of nonfluorinated PNA. In conjunction with our previous work on PNAs fluorinated in backbone and at N-terminus, it is evident that the fluorinated PNAs have potential to emerge as a new class of PNA analogues for applications in functional inhibition of RNA. PMID:27391099
Characterization of Kbot21 Reveals Novel Side Chain Interactions of Scorpion Toxins Inhibiting Voltage-Gated Potassium Channels
ElFessi-Magouri, Rym; Peigneur, Steve; Othman, Houcemeddine; Srairi-Abid, Najet; ElAyeb, Mohamed; Tytgat, Jan; Kharrat, Riadh
Scorpion toxins are important pharmacological tools for probing the physiological roles of ion channels which are involved in many physiological processes and as such have significant therapeutic potential. The discovery of new scorpion toxins with different specificities and affinities is needed to further characterize the physiology of ion channels. In this regard, a new short polypeptide called Kbot21 has been purified to homogeneity from the venom of Buthus occitanus tunetanus scorpion. Kbot21 is structurally related to BmBKTx1 from the venom of the Asian scorpion Buthus martensii Karsch. These two toxins differ by only two residues at position 13 (R /V) and 24 (D/N).Despite their very similar sequences, Kbot21 and BmBKTx1 differ in their electrophysiological activities. Kbot21 targets KV channel subtypes whereas BmBKTx1 is active on both big conductance (BK) and small conductance (SK) Ca2+-activated K+ channel subtypes, but has no effects on Kv channel subtypes. The docking model of Kbot21 with the Kv1.2 channel shows that the D24 and R13 side-chain of Kbot21 are critical for its interaction with KV channels. PMID:26398235
The Identification of Two Arabinosyltransferases from Tomato Reveals Functional Equivalency of Xyloglucan Side Chain Substituents1[W][OPEN
Schultink, Alex; Cheng, Kun; Park, Yong Bum; Cosgrove, Daniel J.; Pauly, Markus
Xyloglucan (XyG) is the dominant hemicellulose present in the primary cell walls of dicotyledonous plants. Unlike Arabidopsis (Arabidopsis thaliana) XyG, which contains galactosyl and fucosyl substituents, tomato (Solanum lycopersicum) XyG contains arabinofuranosyl residues. To investigate the biological function of these differing substituents, we used a functional complementation approach. Candidate glycosyltransferases were identified from tomato by using comparative genomics with known XyG galactosyltransferase genes from Arabidopsis. These candidate genes were expressed in an Arabidopsis mutant lacking XyG galactosylation, and two of them resulted in the production of arabinosylated XyG, a structure not previously found in this plant species. These genes may therefore encode XyG arabinofuranosyltransferases. Moreover, the addition of arabinofuranosyl residues to the XyG of this Arabidopsis mutant rescued a growth and cell wall biomechanics phenotype, demonstrating that the function of XyG in plant growth, development, and mechanics has considerable flexibility in terms of the specific residues in the side chains. These experiments also highlight the potential of reengineering the sugar substituents on plant wall polysaccharides without compromising growth or viability. PMID:23893172
A Biochemical Abnormality in Cerebrotendinous Xanthomatosis IMPAIRMENT OF BILE ACID BIOSYNTHESIS ASSOCIATED WITH INCOMPLETE DEGRADATION OF THE CHOLESTEROL SIDE CHAIN
Setoguchi, T.; Salen, Gerald; Tint, G. S.; Mosbach, E. H.
Bile acid production in cerebrotendinous xanthomatosis (CTX) is subnormal, yet the activity of cholesterol 7α-hydroxylase, the rate-determining enzyme of bile acid synthesis, is elevated. To explain this discrepancy, bile acid precursors were sought in bile and feces of three CTX subjects. Over 10% of the total sterols excreted in bile and feces consisted of compounds more polar than cholesterol. Chromatographic analysis of the polar fractions in conjunction with gasliquid chromatography (GLC)-mass spectrometry indicated two major constituents, 5β-cholestane-3α,7α,12α,25-tetrol and 5β-cholestane-3α,7α,12α,24ξ,25-pentol. After i.v. injection of [4-14C]cholesterol both bile alcohols were radioactive proving that they were derived from cholesterol. The accumulation of alcohols hydroxylated at C-25 and C-24,25 suggests that decreased bile acid synthesis in CTX results from impaired oxidation of the cholesterol side chain. This finding and the virtual absence of intermediates hydroxylated at C-26 indicate that current views of the major pathway of bile acid synthesis may require revision. PMID:4825231
o-Boronato- and o-Trifluoroborato-Phosphonium Salts Supported by L-α-Amino Acid Side Chain.
Bernard, Julie; Malacea-Kabbara, Raluca; Clemente, Gonçalo S; Burke, Benjamin P; Eymin, Marie-Joëlle; Archibald, Stephen J; Jugé, Sylvain
The synthesis of o-boronato- and o-trifluoroborato-phosphonium salts supported by the L-amino acid side chain is described. The synthesis of these new class of amino acid derivatives was achieved by stereoselective quaternization of o-(pinacolato)boronatophenylphosphine with β- or γ-iodo amino acid derivatives which are prepared from L-serine or L-aspartic acid, respectively. The quaternization of the phosphine was performed using either iodo amino ester or carboxylic acid derivatives. In addition, free carboxylic acid and amine derivatives were obtained by saponification or HCl acidolysis of o-boronato-phosphonium amino esters, respectively. The usefulness of these compounds in peptide coupling was demonstrated by coupling an o-boronato-phosphonium amino ester with an aspartic acid moiety. When the o-boronato-phosphonium amino acid or dipeptide derivatives were mixed with fluoride, the corresponding o-trifluoroborated products were cleanly and rapidly obtained in high isolated yields. The hydrolysis of these compounds at room temperature using a phosphate buffer pH 7/CD3CN mixture has shown only traces of free fluoride F(-) after several days. Finally, a preliminary radiolabeling essay has proven the facile [(18)F]-fluoride incorporation and high stability of the radiolabeled product in aqueous conditions. Indeed, this new class of boron-phosphonium amino acid derivatives shows promising properties for their applications in synthesis and labeling of peptides. PMID:25844635
Synthesis, characterization, conformation and self-assembly behavior of polypeptide-based brush with oligo (ethylene glycol) side chains
NASA Astrophysics Data System (ADS)
Huang, Yugang; Luo, Weiang; Ye, Guodong
A new polypeptide-based copolymer brush composed of poly (γ-propargyl-L-glutamate)-block-poly (propylene oxide)-block-poly (γ-propargyl-L-glutamate) backbone (PPLG-b-PPO-b-PPLG) and oligo (ethylene glycol) (PEG) side-chain was synthesized by combination of N-carboxyanhydride ring-opening polymerization and click chemistry. Nearly 100% grafting efficiency was achieved by copper-catalyzed azide-alkyne Huisgen 1,3-dipolar cycloaddition (CuAAc) reaction. The α-helical conformation adopted by the grafted polypeptide blocks in water was relatively stable and showed a reversible change in a heating-cooling circle from 5 to 70 °C. It displayed weak stability against elevated temperature but still reversible changes in the presence of 0.47 M NaCl. The brushes were amphiphilic and could self-assemble into thermo-sensitive micelles in water. Big micelles could break into small micelles upon heating due to the improved solubility.
Preparation of amphiphilic glycopolymers with flexible long side chain and their use as stabilizer for emulsion polymerization.
Alvárez-Paino, Marta; Juan-Rodríguez, Rafael; Cuervo-Rodríguez, Rocío; Muñoz-Bonilla, Alexandra; Fernández-García, Marta
A glycomonomer was synthesized from poly(ethylene glycol) methacrylate (PEGMA). The terminal hydroxyl moieties were activated with ester groups and subsequently the glucosamine was incorporated forming urethane linkages. The obtained glycomonomer was copolymerized with methyl acrylate by free radical polymerization varying the initial feed composition to produce different amphiphilic glycopolymers. The glycopolymers were then characterized and compared with the homologous glycopolymers based on 2-{[(D-glucosamin-2-N-yl)carbonyl]oxy}ethyl methacrylate. Both series of glycopolymers were used in emulsion polymerization of methyl acrylate as stabilizers without the addition of any cosurfactant. Although high conversions were not achieved with any of the employed surfactant, the glycopolymers provide good colloidal stability, spherical, monodisperse and small latex particles in comparison with the surfactant-free emulsion polymerization. The latex particles stabilized with the glycosurfactant based on PEGMA, containing a flexible spacer between the backbone and the glucosamine, lead to smooth films whereas the short side chain surfactant from 2-hydroxyethyl methacrylate (HEMA), with higher glass transition temperature, restricts the coalescence of particles and, therefore, the film formation. Moreover, the surface bioactivity of these polymer coatings was examined by analyzing their specific interaction with the lectin, Concanavalin A, Canavalia ensiformis. The specific and successful binding to the Concanavalin A was demonstrated by fluorescence microscopy for both series being more intense with increasing amount of glycounits in the glycopolymer stabilizers. Interestingly, the incorporation of a flexible spacer in the glycopolymer structures enhances the binding activity. PMID:24407696
ABC triblock surface active block copolymer with grafted ethoxylated fluoroalkyl amphiphilic side chains for marine antifouling/fouling-release applications.
Weinman, Craig J; Finlay, John A; Park, Daewon; Paik, Marvin Y; Krishnan, Sitaraman; Sundaram, Harihara S; Dimitriou, Michael; Sohn, Karen E; Callow, Maureen E; Callow, James A; Handlin, Dale L; Willis, Carl L; Kramer, Edward J; Ober, Christopher K
An amphiphilic triblock surface-active block copolymer (SABC) possessing ethoxylated fluoroalkyl side chains was synthesized through the chemical modification of a polystyrene-block-poly(ethylene-ran-butylene)-block-polyisoprene polymer precursor. Bilayer coatings on glass slides consisting of a thin layer of the amphiphilic SABC spray coated on a thick layer of a polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS) thermoplastic elastomer were prepared for biofouling assays with the green alga Ulva and the diatom Navicula. Dynamic water contact angle analysis and X-ray photoelectron spectroscopy (XPS) were used to characterize the surfaces. Additionally, the effect of the Young's modulus of the coating on the release properties of sporelings (young plants) of the green alga Ulva was examined through the use of two different SEBS thermoplastic elastomers possessing modulus values of an order of magnitude in difference. The amphiphilic SABC was found to reduce the settlement density of zoospores of Ulva as well as the strength of attachment of sporelings. The attachment strength of the sporelings was further reduced for the amphiphilic SABC on the "low"-modulus SEBS base layer. The weaker adhesion of diatoms, relative to a PDMS standard, further highlights the antifouling potential of this amphiphilic triblock hybrid copolymer. PMID:19821626
Neutral Pectin side chains of Amaranth (Amaranthus hypochondriacus) contain long, partially branched Arabinans and short galactans, both with terminal arabinopyranoses.
Wefers, Daniel; Tyl, Catrin E; Bunzel, Mirko
Amaranth is a pseudocereal of high nutritional value, including a high dietary fiber content. Amaranth dietary fiber was suggested to contain large amounts of neutral rhamnogalacturonan I side chains. In this study, endo-arabinanase and endo-galactanase were used to liberate arabinan and galactan oligosaccharides from amaranth fiber. The liberated oligosaccharides were identified by high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and HPLC-MS(n) using standard compounds, which were isolated from amaranth, sugar beet, potato, and red clover sprouts and characterized by one- and two-dimensional NMR spectroscopy. It was demonstrated that insoluble amaranth arabinans have linear and branched areas, with the O-3 position being the dominant branching point. Minor amounts of branches at position O-2 and double substitution were also found. Amaranth arabinans were also demonstrated to contain terminal α-(1→5)-linked l-arabinopyranose units. In addition, it was evidenced that galactans from amaranth seeds are composed of β-(1→4)-linked d-galactopyranose units, which can also be terminated with l-arabinopyranose units. In direct comparison to structural elucidation of amaranth fiber by using methylation analysis, the advantage of the enzymatic approach over methylation analysis was demonstrated. PMID:25529336
Microbial side-chain cleavage of phytosterols by mycobacteria in vegetable oil/aqueous two-phase system.
Xu, Yang-Guang; Guan, Yi-Xin; Wang, Hai-Qing; Yao, Shan-Jing
Microbial side-chain cleavage of natural sterols to 4-androstene-3,17-dione (AD) and 1,4-androstadiene-3,17-dione (ADD) by Mycobacteria has received much attention in pharmaceutical industry, while low yield of the reaction owing to the strong hydrophobicity of sterols is a tough problem to be solved urgently. Eight kinds of vegetable oils, i.e., sunflower, peanut, corn, olive, linseed, walnut, grape seed, and rice oil, were used to construct oil/aqueous biphasic systems in the biotransformation of phytosterols by Mycobacterium sp. MB 3683 cells. The results indicated that vegetable oils are suitable for phytosterol biotransformation. Specially, the yield of AD carried out in sunflower biphasic system (phase ratio of 1:9, oil to aqueous) was greatly increased to 84.8 % with 10 g/L feeding concentration after 120-h transformation at 30 °C and 200 rpm. Distribution coefficients of AD in different oil/aqueous systems were also determined. Because vegetable oils are of low cost and because of their eco-friendly characters, there is a great potential for the application of oil/aqueous two-phase systems in bacteria whole cell biocatalysis. PMID:25082765
Conjugated polymelectrolyte assembly at water-oil interfaces
NASA Astrophysics Data System (ADS)
Liu, Feng; Huang, Caili; Thomas, Russell; Russell Team
Conjugated polyelectrolytes featured with conjugated backbone and functional side chains are interesting optoelectronic materials and widely used to modify electrodes in electronic devices such as light emitting diodes and solar cells to enhance device performance. Conjugated polyelectrolyte can be designed to have alternating hydrophilic and hydrophobic side chains, and thus inducing interesting surface and interface properties. In this work, we using polyfluorene based material, to study its behavior at water-toluene interface. The aliphatic side-chains will favorably interact with toluene, and amine side-chains will interact with water, making this material a good surfactant. At interface the polymer chain is stretched to a Janus type of geometry. Flattened molecules will assemble into ultra thin films via pi-pi intermolecular stacking, and thus creating barriers between liquids. When liquid volume is reduced, jamming at interface will show up. These properties are strongly affected by the environment of the liquids, such as temperature and PH values, and polyelectrolyte diffusion to interfaces. This study leads to new methods to structure liquids using single component, which can be extended to applications such as electro-spinning or fabricate flow devices.
Calcitriol derivatives with two different side chains at C-20. V. Potent Inhibitors of Mammary Carcinogenesis and Inducers of Leukemia Differentiation
Maehr, Hubert; Lee, Hong Jin; Perry, Bradford; Suh, Nanjoo; Uskokovic, Milan R.
Calcitriol is implicated in many cellular functions including cellular growth and differentiation thus explaining its anti-tumor effects. It was shown that gemini, the calcitriol derivative containing two side chain at C20, is also active in gene transcription with enhanced anti-tumor activity. We have now further optimized both the A-ring and the two side chains. The chemical structures of the resulting 18 geminis were correlated with biological activities. Those containing the 1α-fluoro A-ring are the least active. Those featuring 23-yne and 23(E) side-chains are generally more active in human breast cancer-cell growth inhibition and human leukemia-cell differentiation induction than their 23(Z) counterparts. Based on these evaluations we selected as lead compound a 20(R) gemini, related to calcitriol in terms of it's A-ring, where one side chain was modified by introduction of a 23-yne function and replacement of the geminal methyl groups with trifluoromethyl groups, the other created by extension of C21 with a 3-hydroxy-3-trideuteromethyl-4,4,4-trideutero-butyl moiety. PMID:19685888
Probing the effects of the ester functional group, alkyl side chain length and anions on the bulk nanostructure of ionic liquids: a computational study.
Fakhraee, Mostafa; Gholami, Mohammad Reza
The effects of ester addition on nanostructural properties of biodegradable ILs composed of 1-alkoxycarbonyl-3-alkyl-imidazolium cations ([C1COOCnC1im](+), n = 1, 2, 4) combined with [Br](-), [NO3](-), [BF4](-), [PF6](-), [TfO](-), and [Tf2N](-) were explored by using the molecular dynamics (MD) simulations and quantum theory of atoms in molecules (QTAIM) analysis at 400 K. Various thermodynamic properties of these ILs were extensively computed in our earlier work (Ind. Eng. Chem. Res., 2015, 54, 11678-11700). Nano-scale segregation analysis demonstrates the formation of a small spherical island-like hydrocarbon within the continuous ionic domain for ILs with short alkyl side chain ([C1COOC1C1im]), and a sponge-like nanostructure for the compound with long alkyl side chain ([C1COOC4C1im]). Ester-functionalized ILs with ethyl side chain ([C1COOC2C1im]) are the turning point between two different morphologies. Non-polar channels were observed for [C1COOC4C1im] ILs composed of smaller anions such as [Br] and [NO3], whereas clustering organization was found for the other anions. Formation of the spherical micelle-like nanostructure was seen for lengthened cations. Finally, the incorporation of an ester group into the alkyl side chain of the cation leads to stronger segregation between charged and uncharged networks, which consequently increased the possibility of self-assembly and micelle formation. PMID:27001746
Methanol to olefin Conversion on HSAPO-34 zeolite from periodic density functional theory calculations: a complete cycle of side chain hydrocarbon pool mechanism
Wang, C.M.; Wang, Y.D.; Xie, Z.K.; Liu, Z.P.
For its unique position in the coal chemical industry, the methanol to olefin (MTO) reaction has been a hot topic in zeolite catalysis. Due to the complexities of catalyst structure and reaction networks, many questions such as how the olefin chain is built from methanol remain elusive. On the basis of periodic density functional theory calculations, this work establishes the first complete catalytic cycle for MTO reaction via hexamethylbenzene (HMB) trapped in HSAPO-34 zeolite based on the so-called side chain hydrocarbon pool mechanism. The cycle starts from the methylation of HMB that leads to heptamethylbenzenium ion (heptaMB{sup +}) intermediate. This is then followed by the growth of side chain via repeated deprotonation of benzenium ions and methylation of the exocyclic double bond. Ethene and propene can finally be released from the side ethyl and isopropyl groups of benzenium ions by deprotonation and subsequent protonation steps. We demonstrate that (i) HMB/HSAPO-34 only yields propene as the primary product based on the side chain hydrocarbon pool mechanism and (ii) an indirect proton-shift step mediated by water that is always available in the system is energetically more favorable than the traditionally regarded internal hydrogen-shift step. Finally, the implications of our results toward understanding the effect of acidity of zeolite on MTO activity are also discussed.
Compounds having aromatic rings and side-chain amide-functionality and a method for transporting monovalent anions across biological membranes using the same
Davis, Jeffery T.; Sidorov, Vladimir; Kotch, Frank W.
A compound containing at least two aromatic rings covalently bonded together, with each aromatic ring containing at least one oxyacetamide-based side chain, the compound being capable of forming a chloride ion channel across a lipid bilayer, and transporting chloride ion across the lipid bilayer.
Backbone and side-chain (1)H, (15)N, (13)C assignment and secondary structure of BPSL1445 from Burkholderia pseudomallei.
Quilici, Giacomo; Berardi, Andrea; Gaudesi, Davide; Gourlay, Louise J; Bolognesi, Martino; Musco, Giovanna
BPSL1445 is a lipoprotein produced by the Gram-negative bacterium Burkholderia pseudomallei (B. pseudomallei), the etiological agent of melioidosis. Immunodetection assays against sera patients using protein microarray suggest BPSL1445 involvement in melioidosis. Herein we report backbone, side chain NMR assignment and secondary structure for the recombinant protein. PMID:25893672
Controlling Molecular Ordering in Solution-State Conjugated Polymers
Zhu, Jiahua; Han, Youngkyu; Kumar, Rajeev; Hong, Kunlun; Bonnesen, Peter V.; Sumpter, Bobby G.; Smith, Gregory Scott; Ivanov, Ilia N.; Do, Changwoo
Rationally encoding molecular interactions that can control the assembly structure and functional expression in solution of conjugated polymers holds great potential for enabling optimal organic optoelectronic and sensory materials. In this work, we show that thermally-controlled and surfactant-guided assembly of water-soluble conjugated polymers in aqueous solution is a simple and effective strategy to generate optoelectronic materials with desired molecular ordering. We have studied a conjugated polymer consisting of a hydrophobic thiophene backbone and hydrophilic, thermo-responsive ethylene oxide side groups, which shows a step-wise, multi-dimensional assembly in water. By incorporating the polymer into phase-segregated domains of an amphiphilic surfactant in solution, we demonstrate that both chain conformation and degree of molecular ordering of the conjugated polymer can be tuned in hexagonal, micellar and lamellar phases of the surfactant solution. The controlled molecular ordering in conjugated polymer assembly is demonstrated as a key factor determining the electronic interaction and optical function.
Simple physics-based analytical formulas for the potentials of mean force for the interaction of amino acid side chains in water. IV. Pairs of different hydrophobic side chains.
Makowski, Mariusz; Sobolewski, Emil; Czaplewski, Cezary; Ołdziej, Stanisław; Liwo, Adam; Scheraga, Harold A
The potentials of mean force of 21 heterodimers of the molecules modeling hydrophobic amino acid side chains: ethane (for alanine), propane (for proline), isobutane (for valine), isopentane (for leucine and isoleucine), ethylbenzene (for phenylalanine), methyl propyl sulfide (for methionine), and indole (for tryptophane) were determined by umbrella-sampling molecular dynamics simulations in explicit water as functions of distance and orientation. Analytical expressions consisting of the Gay-Berne term to represent effective van der Waals interactions and the cavity term proposed in our earlier work were fitted to the potentials of mean force. The positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the orientation of the molecules, are well represented by the analytical expressions for all systems; large deviations between the MD-determined PMF and the analytical approximations are observed for pairs involving the least spheroidal solutes: ethylbenzene, indole, and methyl propyl sulfide at short distances at which the PMF is high and, consequently, these regions are rarely visited. When data from the PMF within only 10 kcal/mol above the global minimum are considered, the standard deviation between the MD-determined and the fitted PMF is from 0.25 to 0.55 kcal/mol (the relative standard deviation being from 4% to 8%); it is larger for pairs involving nonspherical solute molecules. The free energies of contact computed from the PMF surfaces are well correlated with those determined from protein-crystal data with a slope close to that relating the free energies of transfer of amino acids (from water to n-octanol) to the average contact free energies determined from protein-crystal data. These observations justify future use of the determined potentials in coarse-grained protein-folding simulations. PMID:18700740
Simple Physics-Based Analytical Formulas for the Potentials of Mean Force for the Interaction of Amino Acid Side Chains in Water. IV. Pairs of Different Hydrophobic Side Chains
Makowski, Mariusz; Sobolewski, Emil; Czaplewski, Cezary; Ołdziej, Stanisław; Liwo, Adam; Scheraga, Harold A.
The potentials of mean force of 21 heterodimers of the molecules modeling hydrophobic amino acid side chains: ethane (for alanine), propane (for proline), isobutane (for valine), isopentane (for leucine and isoleucine), ethylbenzene (for phenylalanine), methyl propyl sulfide (for methionine), and indole (for tryptophane) were determined by umbrella-sampling molecular dynamics simulations in explicit water as functions of distance and orientation. Analytical expressions consisting of the Gay–Berne term to represent effective van der Waals interactions and the cavity term proposed in our earlier work were fitted to the potentials of mean force. The positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the orientation of the molecules, are well represented by the analytical expressions for all systems; large deviations between the MD-determined PMF and the analytical approximations are observed for pairs involving the least spheroidal solutes: ethylbenzene, indole, and methyl propyl sulfide at short distances at which the PMF is high and, consequently, these regions are rarely visited. When data from the PMF within only 10 kcal/mol above the global minimum are considered, the standard deviation between the MD-determined and the fitted PMF is from 0.25 to 0.55 kcal/mol (the relative standard deviation being from 4% to 8%); it is larger for pairs involving nonspherical solute molecules. The free energies of contact computed from the PMF surfaces are well correlated with those determined from protein–crystal data with a slope close to that relating the free energies of transfer of amino acids (from water to n-octanol) to the average contact free energies determined from protein–crystal data. These observations justify future use of the determined potentials in coarse-grained protein-folding simulations. PMID:18700740
High-Field-Effect Mobility of Low-Crystallinity Conjugated Polymers with Localized Aggregates.
Son, Sung Y; Kim, Yebyeol; Lee, Junwoo; Lee, Gang-Young; Park, Won-Tae; Noh, Yong-Young; Park, Chan E; Park, Taiho
Charge carriers typically move faster in crystalline regions than in amorphous regions in conjugated polymers because polymer chains adopt a regular arrangement resulting in a high degree of π-π stacking in crystalline regions. In contrast, the random polymer chain orientation in amorphous regions hinders connectivity between conjugated backbones; thus, it hinders charge carrier delocalization. Various studies have attempted to enhance charge carrier transport by increasing crystallinity. However, these approaches are inevitably limited by the semicrystalline nature of conjugated polymers. Moreover, high-crystallinity conjugated polymers have proven inadequate for soft electronics applications because of their poor mechanical resilience. Increasing the polymer chain connectivity by forming localized aggregates via π-orbital overlap among several conjugated backbones in amorphous regions provides a more effective approach to efficient charge carrier transport. A simple strategy relying on the density of random copolymer alkyl side chains was developed to generate these localized aggregates. In this strategy, steric hindrance caused by these side chains was modulated to change their density. Interestingly, a random polymer exhibiting low alkyl side chain density and crystallinity displayed greatly enhanced field-effect mobility (1.37 cm(2)/(V·s)) compared with highly crystalline poly(3-hexylthiophene). PMID:27149835
Amino acid side chain induced selectivity in the hydrolysis of peptides catalyzed by a Zr(IV)-substituted Wells-Dawson type polyoxometalate.
Vanhaecht, Stef; Absillis, Gregory; Parac-Vogt, Tatjana N
In this paper the reactivity of K15H[Zr(α2-P2W17O61)2]·25H2O (1), a Zr(IV)-substituted Wells-Dawson polyoxometalate, is examined towards a series of Gly-Aa, Aa-Gly or Aa-Ser dipeptides, in which the nature and the size of the Aa amino acid side chain were varied. The rate of peptide bond hydrolysis, determined by (1)H NMR experiments, in Gly-Aa dipeptides is strongly dependent on the molecular volume and the chemical structure of the Aa side chain. When the volume of the aliphatic side chain of the Aa residue in Gly-Aa increased, a clear decrease in the hydrolysis rate was observed. Replacing one α-H in the C-terminal Gly residue of Gly-Gly by a methyl group (Gly-Ala) resulted in a 6-fold reactivity decrease, pointing towards the importance of steric factors for efficient peptide bond hydrolysis. The rate constants for peptide bond hydrolysis in Gly-Aa dipeptides at pD 5.0 and 60 °C ranged from 208.0 ± 15.6 × 10(-6) min(-1) for Gly-Ser to 5.0 ± 1.0 × 10(-6) min(-1) for Gly-Glu, reflecting the influence of the different nature of the amino acid side chains on the hydrolysis rate. Faster hydrolysis was observed for peptides containing Ser and Thr since the hydroxyl group in their side chain is able to facilitate amide bond hydrolysis by promoting an N→O acyl rearrangement. Peptides containing positively charged side chains at pD 5.0 show enhanced hydrolysis rates as a result of the secondary electrostatic interactions with the negatively charged surface of the polyoxometalate, which stabilize the peptide-polyoxometalate complex. A slow hydrolysis rate was observed for Gly-Glu, because of the preferential coordination of the carboxylate group in the side chain of Glu to Zr(IV), which prevents coordination of the peptide carbonyl group and its activation towards hydrolysis. PMID:24018583
π-conjugation and conformation in a semiconducting polymer: small angle x-ray scattering study
NASA Astrophysics Data System (ADS)
Choudhury, Paramita Kar; Bagchi, Debjani; Menon, Reghu
Small angle x-ray scattering (SAXS) in a poly[2-methoxy-5-(2'-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV) solution has shown the important role of π-electron conjugation in controlling the chain conformation and assembly. By increasing the extent of conjugation from 30 to 100%, the persistence length (lp) increases from 20 to 66 Å. Moreover, a pronounced second peak in the pair distribution function has been observed in a fully conjugated chain, at larger length scales. This feature indicates that the chain segments tend to self-assemble as the conjugation along the chain increases. Xylene enhances the rigidity of the PPV backbone to yield extended structures, while tetrahydrofuran solvates the side groups to form compact coils in which the lp is much shorter.
Contributions of a disulfide bond and a reduced cysteine side chain to the intrinsic activity of the high-density lipoprotein receptor SR-BI.
Yu, Miao; Lau, Thomas Y; Carr, Steven A; Krieger, Monty
The high-density lipoprotein (HDL) receptor scavenger receptor class B, type I (SR-BI), binds HDL and mediates selective cholesteryl ester uptake. SR-BI's structure and mechanism are poorly understood. We used mass spectrometry to assign the two disulfide bonds in SR-BI that connect cysteines within the conserved Cys(321)-Pro(322)-Cys(323) (CPC) motif and connect Cys(280) to Cys(334). We used site-specific mutagenesis to evaluate the contributions of the CPC motif and the side chain of extracellular Cys(384) to HDL binding and lipid uptake. The effects of CPC mutations on activity were context-dependent. Full wild-type (WT) activity required Pro(322) and Cys(323) only when Cys(321) was present. Reduced intrinsic activities were observed for CXC and CPX, but not XXC, XPX, or XXX mutants (X ≠ WT residue). Apparently, a free thiol side chain at position 321 that cannot form an intra-CPC disulfide bond with Cys(323) is deleterious, perhaps because of aberrant disulfide bond formation. Pro(322) may stabilize an otherwise strained CPC disulfide bond, thus supporting WT activity, but this disulfide bond is not absolutely required for normal activity. C(384)X (X = S, T, L, Y, G, or A) mutants exhibited altered activities that varied with the side chain's size: larger side chains phenocopied WT SR-BI treated with its thiosemicarbazone inhibitor BLT-1 (enhanced binding, weakened uptake); smaller side chains produced almost inverse effects (increased uptake:binding ratio). C(384)X mutants were BLT-1-resistant, supporting the proposal that Cys(384)'s thiol interacts with BLT-1. We discuss the implications of our findings on the functions of the extracellular loop cysteines in SR-BI and compare our results to those presented by other laboratories. PMID:23205738
Contributions of a disulfide bond and a reduced cysteine side chain to the intrinsic activity of the HDL receptor SR-BI
Yu, Miao; Lau, Thomas Y.; Carr, Steven A.; Krieger, Monty
The high density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), binds HDL and mediates selective cholesteryl ester uptake. SR-BI's structure and mechanism are poorly understood. We used mass spectrometry to assign the two disulfide bonds in SR-BI that connect cysteines within the conserved Cys321-Pro322-Cys323 (CPC) motif and connect Cys280 to Cys334. We used site-specific mutagenesis to evaluate the contributions of the CPC motif and the side chain of extracellular Cys384 to HDL binding and lipid uptake. The effects of CPC mutations on activity were context dependent. Full wild-type (WT) activity required Pro322 and Cys323 only when Cys321 was present. Reduced intrinsic activities were observed for CXC and CPX, but not XXC, XPX or XXX mutants (X≠WT residue). Apparently, a free thiol side chain at position 321 that cannot form an intra-CPC disulfide bond with Cys323 is deleterious, perhaps because of aberrant disulfide bond formation. Pro322 may stabilize an otherwise strained CPC disulfide bond, thus supporting WT activity, but this disulfide bond is not absolutely required for activity. C384X (X=S,T,L,Y,G,A) mutants exhibited altered activities that varied with the side chain's size: larger side chains phenocopied WT SR-BI treated with its thiosemicarbazone inhibitor BLT-1 (increased binding, decreased uptake); smaller side chains produced almost inverse effects (increased uptake:binding ratio). C384X mutants were BLT-1 resistant, supporting the proposal that Cys384's thiol interacts with BLT-1. We discuss the implications of our findings on the functions of the extracellular loop cysteines in SR-BI and compare our results to those presented by other laboratories. PMID:23205738
Evaluating Force Fields for the Computational Prediction of Ionized Arginine and Lysine Side-Chains Partitioning into Lipid Bilayers and Octanol.
Sun, Delin; Forsman, Jan; Woodward, Clifford E
Abundant peptides and proteins containing arginine (Arg) and lysine (Lys) amino acids can apparently permeate cell membranes with ease. However, the mechanisms by which these peptides and proteins succeed in traversing the free energy barrier imposed by cell membranes remain largely unestablished. Precise thermodynamic studies (both theoretical and experimental) on the interactions of Arg and Lys residues with model lipid bilayers can provide valuable clues to the efficacy of these cationic peptides and proteins. We have carried out molecular dynamics simulations to calculate the interactions of ionized Arg and Lys side-chains with the zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayer for 10 widely used lipid/protein force fields: CHARMM36/CHARMM36, SLIPID/AMBER99SB-ILDN, OPLS-AA/OPLS-AA, Berger/OPLS-AA, Berger/GROMOS87, Berger/GROMOS53A6, GROMOS53A6/GROMOS53A6, nonpolarizable MARTINI, polarizable MARTINI, and BMW MARTINI. We performed umbrella sampling simulations to obtain the potential of mean force for Arg and Lys side-chains partitioning from water to the bilayer interior. We found significant differences between the force fields, both for the interactions between side-chains and bilayer surface, as well as the free energy cost for placing the side-chain at the center of the bilayer. These simulation results were compared with the Wimley-White interfacial scale. We also calculated the free energy cost for transferring ionized Arg and Lys side-chains from water to both dry and wet octanol. Our simulations reveal rapid diffusion of water molecules into octanol whereby the equilibrium mole fraction of water in the wet octanol phase was ∼25%. Surprisingly, our free energy calculations found that the high water content in wet octanol lowered the water-to-octanol partitioning free energies for cationic residues by only 0.6 to 0.7 kcal/mol. PMID:26574387
Influence of the degree of unsaturation of the acyl side chain upon the interaction of analogues of 1-arachidonoylglycerol with monoacylglycerol lipase and fatty acid amide hydrolase
Vandevoorde, Severine; Saha, Bijali; Mahadevan, Anu; Razdan, Raj K.; Pertwee, Roger G.; Martin, Billy R.; Fowler, Christopher J. . E-mail: email@example.com
Little is known as to the structural requirements of the acyl side chain for interaction of acylglycerols with monoacylglycerol lipase (MAGL), the enzyme chiefly responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain. In the present study, a series of twelve analogues of 1-AG (the more stable regioisomer of 2-AG) were investigated with respect to their ability to inhibit the metabolism of 2-oleoylglycerol by cytosolic and membrane-bound MAGL. In addition, the ability of the compounds to inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) was investigated. For cytosolic MAGL, compounds with 20 carbon atoms in the acyl chain and 2-5 unsaturated bonds inhibited the hydrolysis of 2-oleoylglycerol with similar potencies (IC{sub 50} values in the range 5.1-8.2 {mu}M), whereas the two compounds with a single unsaturated bond were less potent (IC{sub 50} values 19 and 21 {mu}M). The fully saturated analogue 1-monoarachidin did not inhibit the enzyme, whereas the lower side chain analogues 1-monopalmitin and 1-monomyristin inhibited the enzyme with IC{sub 50} values of 12 and 32 {mu}M, respectively. The 22-carbon chain analogue of 1-AG was also potent (IC{sub 50} value 4.5 {mu}M). Introduction of an {alpha}-methyl group for the C20:4, C20:3, and C22:4 compounds did not affect potency in a consistent manner. For the FAAH and the membrane-bound MAGL, there was no obvious relationship between the degree of unsaturation of the acyl side chain and the ability to inhibit the enzymes. It is concluded that increasing the number of unsaturated bonds on the acyl side chain of 1-AG from 1 to 5 has little effect on the affinity of acylglycerols for cytosolic MAGL.
Enhanced photophysics of conjugated polymers
Chen, Liaohai; Xu, Su; McBranch, Duncan; Whitten, David
The addition of oppositely charged surfactant to fluorescent ionic conjugated polymer forms a polymer-surfactant complex that exhibits at least one improved photophysical property. The conjugated polymer is a fluorescent ionic polymer that typically has at least one ionic side chain or moiety that interacts with the specific surfactant selected. The photophysical property improvements may include increased fluorescence quantum efficiency, wavelength-independent emission and absorption spectra, and more stable fluorescence decay kinetics. The complexation typically occurs in a solution of a polar solvent in which the polymer and surfactant are soluble, but it may also occur in a mixture of solvents. The solution is commonly prepared with a surfactant molecule:monomer repeat unit of polymer ratio ranging from about 1:100 to about 1:1. A polymer-surfactant complex precipitate is formed as the ratio approaches 1:1. This precipitate is recoverable and usable in many forms.
Autoantibodies against Cytochrome P450 Side-Chain Cleavage Enzyme in Dogs (Canis lupus familiaris) Affected with Hypoadrenocorticism (Addison's Disease).
Boag, Alisdair M; Christie, Michael R; McLaughlin, Kerry A; Syme, Harriet M; Graham, Peter; Catchpole, Brian
Canine hypoadrenocorticism likely arises from immune-mediated destruction of adrenocortical tissue, leading to glucocorticoid and mineralocorticoid deficiency. In humans with autoimmune Addison's disease (AAD) or autoimmune polyendocrine syndrome (APS), circulating autoantibodies have been demonstrated against enzymes associated with adrenal steroid synthesis. The current study investigates autoantibodies against steroid synthesis enzymes in dogs with spontaneous hypoadrenocorticism. Coding regions of canine CYP21A2 (21-hydroxylase; 21-OH), CYP17A1 (17-hydroxylase; 17-OH), CYP11A1 (P450 side-chain cleavage enzyme; P450scc) and HSD3B2 (3β hydroxysteroid dehydrogenase; 3βHSD) were amplified, cloned and expressed as 35S-methionine radiolabelled recombinant protein. In a pilot study, serum samples from 20 dogs with hypoadrenocorticism and four unaffected control dogs were screened by radio-immunoprecipitation assay. There was no evidence of reactivity against 21-OH, 17-OH or 3βHSD, but five dogs with hypoadrenocorticism showed immunoreactivity to P450scc compared with controls. Serum samples were subsequently obtained from 213 dogs diagnosed with hypoadrenocorticism and 110 dogs from a hospital control population. Thirty control dogs were randomly selected to establish a threshold for antibody positivity (mean + 3 × standard deviation). Dogs with hypoadrenocorticism were more likely to be P450scc autoantibody positive than hospital controls (24% vs. 1.2%, respectively; p = 0.0016). Sex was significantly associated with the presence of P450scc autoantibodies in the case population, with 30% of females testing positive compared with 17% of males (p = 0.037). Significant associations with breed (p = 0.015) and DLA-type (DQA1*006:01 allele; p = 0.017) were also found. This cross-sectional study indicates that P450scc autoantibodies are present in a proportion of dogs affected with hypoadrenocorticism. PMID:26618927
Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents
Rohloff, John C; Gelinas, Amy D; Jarvis, Thale C; Ochsner, Urs A; Schneider, Daniel J; Gold, Larry; Janjic, Nebojsa
Limited chemical diversity of nucleic acid libraries has long been suspected to be a major constraining factor in the overall success of SELEX (Systematic Evolution of Ligands by EXponential enrichment). Despite this constraint, SELEX has enjoyed considerable success over the past quarter of a century as a result of the enormous size of starting libraries and conformational richness of nucleic acids. With judicious introduction of functional groups absent in natural nucleic acids, the "diversity gap" between nucleic acid–based ligands and protein-based ligands can be substantially bridged, to generate a new class of ligands that represent the best of both worlds. We have explored the effect of various functional groups at the 5-position of uracil and found that hydrophobic aromatic side chains have the most profound influence on the success rate of SELEX and allow the identification of ligands with very low dissociation rate constants (named Slow Off-rate Modified Aptamers or SOMAmers). Such modified nucleotides create unique intramolecular motifs and make direct contacts with proteins. Importantly, SOMAmers engage their protein targets with surfaces that have significantly more hydrophobic character compared with conventional aptamers, thereby increasing the range of epitopes that are available for binding. These improvements have enabled us to build a collection of SOMAmers to over 3,000 human proteins encompassing major families such as growth factors, cytokines, enzymes, hormones, and receptors, with additional SOMAmers aimed at pathogen and rodent proteins. Such a large and growing collection of exquisite affinity reagents expands the scope of possible applications in diagnostics and therapeutics. PMID:25291143
Direct NMR observation and pKa determination of the Asp102 side chain in a serine protease.
Everill, Paul; Sudmeier, James L; Bachovchin, William W
The pK(a) value of aspartic acid in the catalytic triad of serine proteases has been a pivotal element in essentially every mechanism proposed for these enzymes over the past 40 years, but has, until now, eluded direct determination. Here, we have used the multinuclear 3D-NMR pulse programs HCACO and HCCH-TOCSY to directly identify and study the side-chain resonances of the aspartate and glutamate residues in uniformly (13)C-labeled α-lytic protease. Resonances from four of the six residues were detected and assigned, including that of Asp(102), which is notably the weakest of the four. pH titrations have shown all of the carboxylate (13)C signals to have unusually low pK(a) values: 2.0, 3.2, and 1.7 for Glu(129), Glu(174), and Glu(229), respectively, and an upper limit of 1.5 for Asp(102). The multiple H-bonds to Asp(102), long known from X-ray crystal studies, probably account for its unusually low pK(a) value through preferential stabilization of its anionic form. These H-bonds probably also contribute to the weakness of the NMR resonances of Asp(102) by restricting its mobility. The Asp(102)(13)C(γ) atom responds to the ionization of His(57) in the resting enzyme and to the inhibitor-derived oxyanion in a chloromethyl ketone complex, observations that strongly support the assignment. The low pK(a) value of Asp(102) would appear to be incompatible with mechanisms involving strong Asp(102)-His(57) H-bonds or high pK(a) values, but is compatible with mechanisms involving normal Asp(102)-His(57) H-bonds and moving His(57) imidazole rings, such as the reaction-driven ring flip. PMID:22229736
Biosynthesis and incorporation of side-chain-truncated lignin monomers to reduce lignin polymerization and enhance saccharification.
Eudes, Aymerick; George, Anthe; Mukerjee, Purba; Kim, Jin S; Pollet, Brigitte; Benke, Peter I; Yang, Fan; Mitra, Prajakta; Sun, Lan; Cetinkol, Ozgül P; Chabout, Salem; Mouille, Grégory; Soubigou-Taconnat, Ludivine; Balzergue, Sandrine; Singh, Seema; Holmes, Bradley M; Mukhopadhyay, Aindrila; Keasling, Jay D; Simmons, Blake A; Lapierre, Catherine; Ralph, John; Loqué, Dominique
Lignocellulosic biomass is utilized as a renewable feedstock in various agro-industrial activities. Lignin is an aromatic, hydrophobic and mildly branched polymer integrally associated with polysaccharides within the biomass, which negatively affects their extraction and hydrolysis during industrial processing. Engineering the monomer composition of lignins offers an attractive option towards new lignins with reduced recalcitrance. The presented work describes a new strategy developed in Arabidopsis for the overproduction of rare lignin monomers to reduce lignin polymerization degree (DP). Biosynthesis of these 'DP reducers' is achieved by expressing a bacterial hydroxycinnamoyl-CoA hydratase-lyase (HCHL) in lignifying tissues of Arabidopsis inflorescence stems. HCHL cleaves the propanoid side-chain of hydroxycinnamoyl-CoA lignin precursors to produce the corresponding hydroxybenzaldehydes so that plant stems expressing HCHL accumulate in their cell wall higher amounts of hydroxybenzaldehyde and hydroxybenzoate derivatives. Engineered plants with intermediate HCHL activity levels show no reduction in total lignin, sugar content or biomass yield compared with wild-type plants. However, cell wall characterization of extract-free stems by thioacidolysis and by 2D-NMR revealed an increased amount of unusual C₆C₁ lignin monomers most likely linked with lignin as end-groups. Moreover the analysis of lignin isolated from these plants using size-exclusion chromatography revealed a reduced molecular weight. Furthermore, these engineered lines show saccharification improvement of pretreated stem cell walls. Therefore, we conclude that enhancing the biosynthesis and incorporation of C₆C₁ monomers ('DP reducers') into lignin polymers represents a promising strategy to reduce lignin DP and to decrease cell wall recalcitrance to enzymatic hydrolysis. PMID:22458713
Structure and segmental dynamics in amorphous conjugated polymers
NASA Astrophysics Data System (ADS)
Zhan, Pengfei; Maranas, Janna; Gomez, Enrique
Although it is well established that the microstructure strongly affects charge transport in organic semiconductors, the role of fluctuations of the structure on charge mobilities is still not well understood. We have examined the dynamics and structure in amorphous conjugated polymers poly(3-alkylthiophene)s (P3ATs) with neutron and x-ray scattering. We measured the segmental dynamics in amorphous P3ATs with quasi-elastic neutron scattering (QENS). The structure of amorphous P3ATs is measured with small-angle neutron scattering (SANS) and grazing incidence X-ray diffraction (GIXRD). Using SANS, we observe phase separation between the backbone and side-chains in all polymer samples for regiorandom P3ATs. Additionally, the analysis of the QENS data shows that longer side-chains relax faster compared with shorter side-chains and our further analysis of the elastic incoherent structure factor (EISF) suggests that the amplitude of proton motion on the thiophene rings increases by a factor of 3 as the side-chain length increases from 6 to 12, demonstrating that longer side chains lead to enhanced motion of conjugated rings. This work is done under the support of Dow Chemical Company
Unraveling the Nanostructure and Chain Conformation of Peptide-polymer Conjugates in Solution using Small-angle X-ray Scattering
NASA Astrophysics Data System (ADS)
Lund, Reidar; Xu, Ting; Dong, He
For therapeutics, polymer functionalization, often by poly(ethylene glycol), PEG (``PEGylation''), is an effective method to improve the solubility, increase the life time and protect the proteins from the immune system[1]. However it is essential that the proteins maintain their structural integrity in solution- thus the role of the polymer and their interactions with proteins needs to be understood. In this work we show how small-angle X-ray scattering (SAXS) can be used as a powerful technique to characterize the structural components of peptide-polymer conjugates in solution [2, 3]. We specifically show that by applying detailed modelling very detailed structural features can be revealed, including the PEG chain conformation. In the presentation we will provide an overview of the methodology, specifically addressing peptides that form either alpha-helical bundles [2, 3] or beta-sheet structures [4, 5] and relate their structure in solution to their crystal structure.
Non-Monotonic Concentration Effects in the Phase Behavior and Nematic Orders: Mixtures of Side-Chain Liquid Crystalline Polymers and Low-Molecular-Weight Liquid Crystals
NASA Astrophysics Data System (ADS)
Zhuang, Bilin; Wang, Zhen-Gang
Mixtures of side-chain liquid crystal polymers (SCLCPs) and low-molecular-weight liquid crystals (LMWLCs) are novel materials with applications such as optical data storage, non-linear optics, solid polymer electrolytes, chromatography and display materials. Recent experiments showed that the nematic-isotropic transition temperature and the nematic orders of each component vary non-monotonically with concentration. Existing theories, which combine the Flory-Huggins theory for isotropic mixing and the Maier-Saupe theory for nematic order, cannot explain such non-monotonicity. Here, we extend the existing theories by, first, incorporating the local steric constraints between the side-chain and the polymer backbone on the SCLCPs, and second, accounting for the crowding effects at high SCLCP concentrations. The new extended theory is able to resolve the discrepancies between the predictions of existing theories and the experimental observations.
Effects of Side-Chain and Electron Exchange Correlation on the Band Structure of Perylene Diimide Liquid Crystals: A Density Functional Study
Arantes, J. T.; Lima, M. P.; Fazzio, A.; Xiang, H.; Wei, S. H.; Dalpian, G. M.
The structural and electronic properties of perylene diimide liquid crystal PPEEB are studied using ab initio methods based on the density functional theory (DFT). Using available experimental crystallographic data as a guide, we propose a detailed structural model for the packing of solid PPEEB. We find that due to the localized nature of the band edge wave function, theoretical approaches beyond the standard method, such as hybrid functional (PBE0), are required to correctly characterize the band structure of this material. Moreover, unlike previous assumptions, we observe the formation of hydrogen bonds between the side chains of different molecules, which leads to a dispersion of the energy levels. This result indicates that the side chains of the molecular crystal not only are responsible for its structural conformation but also can be used for tuning the electronic and optical properties of these materials.
A Polyurethane Surface Modifier: Contrasting Amphiphilic and Contraphilic Surfaces Driven by block and random Soft Blocks having Trifluoroethoxymethyl and PEG Side Chains
Zhang, Wei; Fujiwara, Tomoko; Taşkent, Hűmeyra; Zheng, Ying; Brunson, Kennard; Gamble, Lara; Wynne, Kenneth J.
A conventional MDI-BD-PTMO polyurethane was modified using 2 wt.% polyurethanes (U) having copolyoxetane soft blocks with hydrophobic 3F, CF3CH2OCH2- and hydrophilic MEn, CH3O(CH2CH2O)nCH2-, n = 3, 7) side chains. In contrast to neat 3F-co-MEn-U, 2 wt.% 3F-co-MEn-U compositions have physically stable morphologies and wetting behavior. Surface composition (XPS) and amphiphilic or contraphilic wetting are controlled by the 3F-co-MEn polyoxetane soft block architecture and MEn side chain length. Importantly, θrec can be tuned for 2 wt.% 3F-co-MEn-U compositions independent of swelling, which is controlled by the bulk polyurethane. AFM imaging led to a new morphological model whereby fluorous/PEG-hard block nano-aggregates combine to form near surface features culminating in micron scale texturing. PMID:24204100
Backbone and side-chain resonance assignment of the A147T polymorph of mouse TSPO in complex with a high-affinity radioligand.
Jaremko, Mariusz; Jaremko, Łukasz; Giller, Karin; Becker, Stefan; Zweckstetter, Markus
The integral polytopic membrane protein TSPO is the target for numerous endogenous and synthetic ligands. However, the affinity of many ligands is influenced by a common polymorphism in TSPO, in which an alanine at position 147 is replaced by threonine, thereby complicating the use of several radioligands for clinical diagnosis. In contrast, the best-characterized TSPO ligand (R)-PK11195 binds with similar affinity to both variants of mitochondrial TSPO (wild-type and A147T variant). Here we report the (1)H, (13)C, (15)N backbone and side-chain resonance assignment of the A147T polymorph of TSPO from Mus Musculus in complex with (R)-PK11195 in DPC detergent micelles. More than 90 % of all resonances were sequence-specifically assigned, demonstrating the ability to obtain high-quality spectral data for both the backbone and the side-chains of medically relevant integral membrane proteins. PMID:26364056
The effect of glutamic acid side chain on acidity constant of lysine in beta-sheet: A density functional theory study
NASA Astrophysics Data System (ADS)
Sargolzaei, M.; Afshar, M.; Sadeghi, M. S.; Kavee, M.
In this work, the possibility of proton transfer between side chain of lysine and glutamic acid in peptide of Glu--Ala-Lys+ was demonstrated using density functional theory (DFT). We have shown that the proton transfer takes place between side chain of glutamic and lysine residues through the hydrogen bond formation. The structures of transition state for proton transfer reaction were detected in gas and solution phases. Our kinetic studies show that the proton transfer reaction rate in gas phase is higher than solution phase. The ionization constant (p K a) value of lysine residue in peptide was estimated 1.039 which is lower than intrinsic p K a of lysine amino acid.
An efficient nitration of light alkanes and the alkyl side-chain of aromatic compounds with nitrogen dioxide and nitric acid catalyzed by N-hydroxyphthalimide.
Nishiwaki, Yoshiki; Sakaguchi, Satoshi; Ishii, Yasutaka
Nitration of light alkanes and the alkyl side-chain of aromatic compounds with NO(2) and HNO(3) was successfully achieved by the use of N-hydroxyphthalimide (NHPI) as a catalyst under relatively mild conditions. For example, the nitration of propane with NO(2) catalyzed by NHPI at 100 degrees C for 14 h gave 2-nitropropane in good yield without formation of 1-nitropropane and cleaved products such as nitroethane and nitromethane. Various aliphatic nitroalkanes, which are difficult to prepare by conventional methods, could be selectively obtained by means of the present methodology by using NHPI as the key catalyst. In addition, the side-chain nitration of alkylbenzenes such as toluene was selectively carried out to lead to alpha-nitrotoluene without the ring nitration. The present reaction provides an efficient selective method for the nitration of light alkanes and alkylbenzenes, which has been very difficult to carry out so far. PMID:12153265
Low half-wave voltage Y-branch electro-optic polymer modulator based on side-chain polyurethane-imide
NASA Astrophysics Data System (ADS)
Tang, Jie; Wang, Long-De; Li, Ruo-Zhou; Zhang, Qiang; Zhang, Tong
A Y-branch electro-optic (EO) polymer modulator has been designed and fabricated. High performance side-chain polyurethane-imide (PUI) with a high EO coefficient of larger than 50 pm/V and a moderate glass-transition temperature (Tg) of 206∘C is used as EO polymer core layer of the modulator. The fabricated phase modulator exhibits a low half-wave voltage of 1.94 V at 1550 nm in single arm modulation with 1 cm EO interaction length and 2 cm total length. The results show that the modulator fabricated by side-chain PUI EO materials possesses potential applications in low driving voltage and low cost optical systems.
Role of the side chain stereochemistry in the α-glucosidase inhibitory activity of kotalanol, a potent natural α-glucosidase inhibitor. Part 2.
Tanabe, Genzoh; Matsuoka, Kanjyun; Yoshinaga, Masahiro; Xie, Weijia; Tsutsui, Nozomi; A Amer, Mumen F; Nakamura, Shinya; Nakanishi, Isao; Wu, Xiaoming; Yoshikawa, Masayuki; Muraoka, Osamu
To examine the role of the side chain of kotalanol (2), a potent natural α-glucosidase inhibitor isolated from Salacia reticulata, on inhibitory activity, four diastereomers (11a-11d) with reversed configuration (S) at the C-4' position in the side chain were synthesized and evaluated. Two of the four (11b and 11d) significantly lost their inhibitory activity against both maltase and sucrase, while the other two (11a and 11c) sustained the inhibitory activity to a considerable extent, showing distinct activity in response to the change of stereochemistry of the hydroxyls at the 5'and 6' positions. Different activities were rationalized with reference to in silico docking studies on these inhibitors with hNtMGAM. Against isomaltase, all four analogs showed potent inhibitory activity as well as 2, and 11b and 11d exhibited enzyme selectivity. PMID:23031648
Side-chain amino-acid-based pH-responsive self-assembled block copolymers for drug delivery and gene transfer.
Kumar, Sonu; Acharya, Rituparna; Chatterji, Urmi; De, Priyadarsi
Developing safe and effective nanocarriers for multitype of delivery system is advantageous for several kinds of successful biomedicinal therapy with the same carrier. In the present study, we have designed amino acid biomolecules derived hybrid block copolymers which can act as a promising vehicle for both drug delivery and gene transfer. Two representative natural chiral amino acid-containing (l-phenylalanine and l-alanine) vinyl monomers were polymerized via reversible addition-fragmentation chain transfer (RAFT) process in the presence of monomethoxy poly(ethylene glycol) based macro-chain transfer agents (mPEGn-CTA) for the synthesis of well-defined side-chain amino-acid-based amphiphilic block copolymers, monomethoxy poly(ethylene glycol)-b-poly(Boc-amino acid methacryloyloxyethyl ester) (mPEGn-b-P(Boc-AA-EMA)). The self-assembled micellar aggregation of these amphiphilic block copolymers were studied by fluorescence spectroscopy, atomic force microscopy (AFM) and scanning electron microscopy (SEM). Potential applications of these hybrid polymers as drug carrier have been demonstrated in vitro by encapsulation of nile red dye or doxorubicin drug into the core of the micellar nanoaggregates. Deprotection of side-chain Boc- groups in the amphiphilic block copolymers subsequently transformed them into double hydrophilic pH-responsive cationic block copolymers having primary amino groups in the side-chain terminal. The DNA binding ability of these cationic block copolymers were further investigated by using agarose gel retardation assay and AFM. The in vitro cytotoxicity assay demonstrated their biocompatible nature and these polymers can serve as "smart" materials for promising bioapplications. PMID:24274731
Modulation of Symmetry-Breaking Intramolecular Charge-Transfer Dynamics Assisted by Pendant Side Chains in π-Linkers in Quadrupolar Diketopyrrolopyrrole Derivatives.
Kim, Woojae; Sung, Jooyoung; Grzybowski, Marek; Gryko, Daniel T; Kim, Dongho
The effect of the length of pendant side chains in centrosymmetric quadrupolar molecules on dynamics of their most perplexing photophysical phenomenon, i.e., symmetry-breaking intramolecular charge transfer, has been discovered. Unexpectedly, considerable influence of length of these pendant side chains in π-linkers arose as a structural factor enabling the control of the degree of fluorescence solvatochromism. The symmetry-breaking intramolecular charge-transfer dynamics has been described on quadrupolar diketopyrrolopyrrole derivatives possessing fluorene moieties as π-linkers and diarylamino groups as electron donors. On the basis of the evolution of transient fluorescence spectra obtained by a femtosecond broadband fluorescence up-conversion spectroscopy, it was found that the relative contribution of diffusive solvation and torsional relaxation in overall spectral relaxation can be modulated by the length of pendant side chain in π-linkers. Consequently, we demonstrated that this modulation plays a significant role in determining the photophysical properties of diketopyrrolopyrroles in a polar medium. PMID:27455383
Photo-aligned blend films of azobenzene-containing polyimides with and without side-chains for inducing inclined alignment of liquid crystal molecules
NASA Astrophysics Data System (ADS)
Usami, Kiyoaki; Sakamoto, Kenji
We have succeeded in controlling the pretilt angle of liquid crystal (LC) molecules over the whole range of 0 to 90° by using photo-aligned blend films of two azobenzene-containing polyimides (Azo-PIs) with and without side-chains. The Azo-PIs were synthesized from pyromellitic dianhydride and a mixture of 4,4'-diaminoazobenzene and 4-(4'-propylbi(cyclohexan)-4-yl)phenyl 3,5-diaminobenzoate (PBCP-DABA). PBCP-DABA is a diamine to introduce a side-chain structure into the polyimide. Defect-free uniform LC alignment was obtained in the pretilt angle (θp) ranges of θp ≤ 11° and θp ≥ 78°. Previously, we reported that the pretilt angle can be controlled using pure photo-aligned films of Azo-PIs with different molar fractions of PBCP-DABA. For the pure photo-aligned films, the defect-free pretilt angle ranges were θp < 5° and θp ≥ 85°. These results suggest that the azimuthal anchoring strength of the blend Azo-PI film is stronger than that of the pure films of Azo-PIs with side-chains, at least for the pretilt angle range from 5 to 11°. We found that the defect-free pretilt angle range can be extended by using the blend Azo-PI films instead of the pure Azo-PI films.
Exploration on natural product anibamine side chain modification toward development of novel CCR5 antagonists and potential anti-prostate cancer agents.
Xu, Guoyan G; Zaidi, Saheem A; Zhang, Feng; Singh, Shilpa; Raborg, Thomas J; Yuan, Yunyun; Zhang, Yan
Prostate cancer is one of the leading causes of death among males in the world. Prostate cancer cells have been shown to express upregulated chemokine receptor CCR5, a G protein-coupled receptor (GPCR) that relates to the inflammation process. Anibamine, a natural product containing a pyridine ring and two aliphatic side chains, was shown to carry a binding affinity of 1 μM at CCR5 as an antagonist with potential anti-cancer activity. However, it is not drug-like according to the Lipinski's rule of five mainly due to its two long aliphatic side chains. In our effort to improve its drug-like property, a series of anibamine derivatives were designed and synthesized by placement of aromatic side chains through an amide linkage to the pyridine ring. The newly synthesized compounds were tested for their CCR5 affinity and antagonism, and potential anti-proliferation activity against prostate cancer cell lines. Basal cytotoxicity was finally studied for compounds showing potent anti-proliferation activity. It was found that compounds with hydrophobic substitutions on the aromatic systems seemed to carry more promising CCR5 binding and prostate cancer cell proliferation inhibition activities. PMID:26096680
Hydrogelation Induced by Change in Hydrophobicity of Amino Acid Side Chain in Fmoc-Functionalised Amino Acid: Significance of Sulfur on Hydrogelation.
Reddy, Samala Murali Mohan; Dorishetty, Pramod; Deshpande, Abhijit P; Shanmugam, Ganesh
Although a few Fmoc-functionalised amino acids (Fmoc-AA) are capable of forming hydrogels, the exact levels of hydrophobicity, hydrogen bonding, and ionic nature of the Fmoc-AA gelator required for hydrogel formation remains uncertain. Here, the role of hydrophobicity of amino acid side chain, particularly in the formation of hydrogel, was studied by using Fmoc-norleucine (Fmoc-Nle) and its simple sulfur analogues such as Fmoc-methionine (Fmoc-M) in which the γCH2 of Fmoc-Nle is replaced by sulfur. Results indicate that Fmoc-M forms thermally reversible hydrogels in water (pH ca. 6.8), whereas Fmoc-Nle fails to display any gelation under similar conditions. The result suggests that substitution of the sulfur atom likely reduces the hydrophobicity of the alkyl side chain in Fmoc-Nle to the optimum level, which is sufficient to induce supramolecular hydrogelation in Fmoc-M. The difference in the self-association behaviour of Fmoc-M and Fmoc-Nle emphasise the importance of weak noncovalent interaction between side chains (in addition to the hydrogen-bond and aromatic interactions) to stabilise supramolecular self-assembly of Fmoc-functionalised compounds. The current observations provide a lead to the design of new sulfur-based low molecular weight gelators for various potential applications. PMID:27017582
Computational modeling of the side chain dihedral angle distributions of methionine using hard-sphere repulsive and short-range attractive interactions
NASA Astrophysics Data System (ADS)
Virrueta, Alejandro; O'Hern, Corey; Regan, Lynne
Methionine (Met) is a versatile amino acid found frequently both in protein cores and at protein-protein interfaces. Thus, a complete description of the structure of Met is tantamount to a fundamental understanding of protein structure and design. In previous work, we showed that our hard-sphere dipeptide model is able to recapitulate the side chain dihedral angle distributions observed in high-resolution protein crystal structures for the 8 amino acids we have studied to date: Val, Thr, Ser, Leu, Ile, Cys, Tyr, and Phe. Using the same approach, we can predict the observed Met side chain dihedral angle distributions P (χ1) and P (χ2) , but not P (χ3) . In this manuscript, we investigate the possible origins of the discrepancy and identify the minimal additions to the hard-sphere dipeptide model necessary to quantitatively predict P (χ3) of Met. We find that applying a Lennard-Jones potential with weak attraction between hydrogen atoms is sufficient to achieve predictions that match the observed χ3 side chain dihedral angle probability distributions for Met, Nle, and Mse without negatively affecting our results for the 8 previously studied amino acids. A. V. is supported by an NSF Graduate Research Fellowship and a Ford Foundation Fellowship.
Effect of side-chain structure of rigid polyimide dispersant on mechanical properties of single-walled carbon nanotube/cyanate ester composite.
Yuan, Wei; Li, Weifeng; Mu, Yuguang; Chan-Park, Mary B
Three kinds of polymer, polyimide without side-chain (PI), polyimide-graft-glyceryl 4-nonylphenyl ether (PI-GNE), and polyimide-graft-bisphenol A diglyceryl acrylate (PI-BDA), have been synthesized and used to disperse single-walled carbon nanotubes (SWNTs) and to improve the interfacial bonding between SWNTs and cyanate ester (CE) matrix. Visual observation, UV-vis-near-IR (UV-vis-NIR) spectra, and atomic force microscopy (AFM) images show that both PI-GNE and PI-BDA are highly effective at dispersing and debundling SWNTs in DMF, whereas PI is less effective. Interaction between SWNTs and PI, PI-GNE or PI-BDA was confirmed by computer simulation and Raman spectra. A series of CE-based composite films reinforced with different loadings of SWNTs, SWNTs/PI, SWNTs/PI-GNE and SWNTs/PI-BDA were prepared by solution casting. It was found that, because of the unique side-chain structure of PI-BDA, SWNTs/PI-BDA disperse better in CE matrix than do SWNTs/PI-GNE, SWNTs/PI, and SWNTs. As a result, SWNTs/PI-BDA/CE composites have the greatest improvement in mechanical properties of the materials tested. These results imply that the choice of side-chain on a dispersant is very important to the dispersion of SWNTs in matrix and the filler/matrix interfacial adhesion, which are two key requirements for achieving effective reinforcement. PMID:21526794
Accessing conjugated polymers with precisely controlled heterobisfunctional chain ends via post-polymerization modification of the OTf group and controlled Pd(0)/t-Bu3P-catalyzed Suzuki cross-coupling polymerization
Hu, Qiao -Sheng; Hong, Kunlun; Zhang, Hong -Hai
In this study, a general strategy toward the synthesis of well-defined conjugated polymers with controlled heterobisfunctional chain ends via combination of controlled Pd(0)/t-Bu3P Suzuki cross-coupling polymerization with the post-polymerization modification of the triflate (OTf) group was disclosed.
Accessing conjugated polymers with precisely controlled heterobisfunctional chain ends via post-polymerization modification of the OTf group and controlled Pd(0)/t-Bu3P-catalyzed Suzuki cross-coupling polymerization
Hu, Qiao -Sheng; Hong, Kunlun; Zhang, Hong -Hai
In this study, a general strategy toward the synthesis of well-defined conjugated polymers with controlled heterobisfunctional chain ends via combination of controlled Pd(0)/t-Bu3P Suzuki cross-coupling polymerization with the post-polymerization modification of the triflate (OTf) group was disclosed.
Structure-activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure 3: role of the length of alditol side chain.
Tsutsui, Nozomi; Tanabe, Genzoh; Morita, Nao; Okayama, Yoshitomo; Kita, Ayako; Sugiura, Reiko; Muraoka, Osamu
Five homologs of a novel glycolipid acremomannolipin A (1a), the potential Ca(2+) signal modulator isolated from Acremonium strictum, bearing alditols of different length (1g-1k) were synthesized by a stereoselective β-mannosylation of appropriately protected mannosyl sulfoxide (2) with five alditols (1g: C2, 1h: C3, 1i: C4, 1j: C5 and 1k: C7 units), and their potential in modulating Ca(2+) signaling were evaluated. Homologs with alditols of more than 4 carbons (1i, 1j and 1k) were equally or more potent than the parent compound (1a) regardless of the length of the alditol chain. Whereas activities of two homologs with shorter chains (1g and 1h) decreased to a considerable extent. The results indicated that the length of the alditol side chain was a crucial determinant for the potent calcium signal modulating activity. PMID:25910586
The effects of side-chain-induced disorder on the emission spectra and quantum yields of oligothiophene nano-aggregates. A combined experimental and MD-TDDFT study
Hong, Jiyun; Jeon, SuKyung; Kim, Janice J.; Devi, Diane; Chacon-Madrid, Kelly; Lee, Wynee; Koo, Seung Moh; Wildeman, Jurjen; Sfeir, Matthew Y.; Peteanu, Linda A.; et al
Oligomeric thiophenes are commonly-used components in organic electronics and solar cells. These molecules stack and/or aggregate readily under the processing conditions used to form thin films for these applications, significantly altering their optical and charge-transport properties. To determine how these effects depend on the substitution pattern of the thiophene main chains, nano-aggregates of three sexi-thiophene (6T) oligomers having different alkyl substitution patterns were formed using solvent poisoning techniques and studied using steady-state and time-resolved emission spectroscopy. The results indicate the substantial role played by the side-chain substituents in determining the emissive properties of these species. Both the measured spectral changesmore » and their dependence on substitution are well modeled by combined quantum chemistry and molecular dynamics simulations. The simulations connect the side-chain-induced disorder, which determines the favorable chain packing configurations within the aggregates, with their measured electronic spectra.« less
Side-chain chi(1) conformations in urea-denatured ubiquitin and protein G from (3)J coupling constants and residual dipolar couplings.
Vajpai, Navratna; Gentner, Martin; Huang, Jie-Rong; Blackledge, Martin; Grzesiek, Stephan
Current NMR information on side-chain conformations of unfolded protein states is sparse due to the poor dispersion particularly of side-chain proton resonances. We present here optimized schemes for the detection of (3)J(HalphaHbeta), (3)J(NHbeta), and (3)J(C'Hbeta) scalar and (1)D(CbetaHbeta) residual dipolar couplings (RDCs) in unfolded proteins. For urea-denatured ubiquitin and protein G, up to six (3)J-couplings to (1)H(beta) are detected, which define the chi(1) angle at very high precision. Interpretation of the (3)J couplings by a model of mixed staggered chi(1) rotamers yields excellent agreement and also provides stereoassignments for (1)H(beta) methylene protons. For all observed amino acids with the exception of leucine, the chemical shift of (1)H(beta3) protons was found downfield from (1)H(beta2). For most residues, the precision of individual chi(1) rotamer populations is better than 2%. The experimental chi(1) rotamer populations are in the vicinity of averages obtained from coil regions in folded protein structures. However, individual variations from these averages of up to 40% are highly significant and indicate sequence- and residue-specific interactions. Particularly strong deviations from the coil average are found for serine and threonine residues, an effect that may be explained by a weakening of side-chain to backbone hydrogen bonds in the urea-denatured state. The measured (1)D(CbetaHbeta) RDCs correlate well with predicted RDCs that were calculated from a sterically aligned coil model ensemble and the (3)J-derived chi(1) rotamer populations. This agreement supports the coil model as a good first approximation of the unfolded state. Deviations between measured and predicted values at certain sequence locations indicate that the description of the local backbone conformations can be improved by incorporation of the RDC information. The ease of detection of a large number of highly precise side-chain RDCs opens the possibility for a more
Outer membrane phospholipase A in phospholipid bilayers: A model system for concerted computational and experimental investigations of amino acid side chain partitioning into lipid bilayers
Fleming, Patrick J.; Freites, J. Alfredo; Moon, C. Preston; Tobias, Douglas J.; Fleming, Karen G.
Understanding the forces that stabilize membrane proteins in their native states is one of the contemporary challenges of biophysics. To date, estimates of side chain partitioning free energies from water to the lipid environment show disparate values between experimental and computational measures. Resolving the disparities is particularly important for understanding the energetic contributions of polar and charged side chains to membrane protein function because of the roles these residue types play in many cellular functions. In general, computational free energy estimates of charged side chain partitioning into bilayers are much larger than experimental measurements. However, the lack of a protein-based experimental system that uses bilayers against which to vet these computational predictions has traditionally been a significant drawback. Moon & Fleming recently published a novel hydrophobicity scale that was derived experimentally by using a host-guest strategy to measure the side chain energetic perturbation due to mutation in the context of a native membrane protein inserted into a phospholipid bilayer. These values are still approximately an order of magnitude smaller than computational estimates derived from molecular dynamics calculations from several independent groups. Here we address this discrepancy by showing that the free energy differences between experiment and computation become much smaller if the appropriate comparisons are drawn, which suggests that the two fields may in fact be converging. In addition, we present an initial computational characterization of the Moon & Fleming experimental system used for the hydrophobicity scale: OmpLA in DLPC bilayers. The hydrophobicity scale used OmpLA position 210 as the guest site, and our preliminary results demonstrate that this position is buried in the center of the DLPC membrane, validating its usage in the experimental studies. We further showed that the introduction of charged Arg at position 210
Polarisabilities of long conjugated chain molecules with density functional response methods: The role of coupled and uncoupled response
Heßelmann, Andreas
The longitudinal component of the dipole-dipole polarisability of polyacetylene molecules containing 4 to 20 carbon atoms has been calculated with density-functional theory (DFT) response methods. In order to analyse the effect of the uncoupled and coupled contributions to the response matrix, a number of different sets of orbitals were combined with different approximations for the Hessian matrix. This revealed a surprising result: a qualitatively correct increase of the polarisability with the chain length can already be reproduced on the uncoupled level if the response matrix is constructed from Hartree-Fock (HF) or exact-exchange (EXX) DFT orbitals. The nonlocal HF and the local EXX exchange potentials both produce a displacement of charge from the chain ends to the centre of the polyacetylene molecule compared to DFT methods using standard exchange-correlation potentials. In this way, the reduced increase of the transition dipole moments along the molecular axis counteracts the decrease of the occupied-virtual orbital energy gaps and leads to a linear dependence of the polarisabilities (normalised by the number of carbon atoms) on the chain length. A new DFT response approach is tested which utilises unitary transformed Hartree-Fock orbitals as input and which resolves the failure of standard DFT response methods.
Polarisabilities of long conjugated chain molecules with density functional response methods: The role of coupled and uncoupled response
NASA Astrophysics Data System (ADS)
Heßelmann, Andreas
The longitudinal component of the dipole-dipole polarisability of polyacetylene molecules containing 4 to 20 carbon atoms has been calculated with density-functional theory (DFT) response methods. In order to analyse the effect of the uncoupled and coupled contributions to the response matrix, a number of different sets of orbitals were combined with different approximations for the Hessian matrix. This revealed a surprising result: a qualitatively correct increase of the polarisability with the chain length can already be reproduced on the uncoupled level if the response matrix is constructed from Hartree-Fock (HF) or exact-exchange (EXX) DFT orbitals. The nonlocal HF and the local EXX exchange potentials both produce a displacement of charge from the chain ends to the centre of the polyacetylene molecule compared to DFT methods using standard exchange-correlation potentials. In this way, the reduced increase of the transition dipole moments along the molecular axis counteracts the decrease of the occupied-virtual orbital energy gaps and leads to a linear dependence of the polarisabilities (normalised by the number of carbon atoms) on the chain length. A new DFT response approach is tested which utilises unitary transformed Hartree-Fock orbitals as input and which resolves the failure of standard DFT response methods.
Clusters of isoleucine, leucine, and valine side chains define cores of stability in high-energy states of globular proteins: Sequence determinants of structure and stability.
Kathuria, Sagar V; Chan, Yvonne H; Nobrega, R Paul; Özen, Ayşegül; Matthews, C Robert
Measurements of protection against exchange of main chain amide hydrogens (NH) with solvent hydrogens in globular proteins have provided remarkable insights into the structures of rare high-energy states that populate their folding free-energy surfaces. Lacking, however, has been a unifying theory that rationalizes these high-energy states in terms of the structures and sequences of their resident proteins. The Branched Aliphatic Side Chain (BASiC) hypothesis has been developed to explain the observed patterns of protection in a pair of TIM barrel proteins. This hypothesis supposes that the side chains of isoleucine, leucine, and valine (ILV) residues often form large hydrophobic clusters that very effectively impede the penetration of water to their underlying hydrogen bond networks and, thereby, enhance the protection against solvent exchange. The linkage between the secondary and tertiary structures enables these ILV clusters to serve as cores of stability in high-energy partially folded states. Statistically significant correlations between the locations of large ILV clusters in native conformations and strong protection against exchange for a variety of motifs reported in the literature support the generality of the BASiC hypothesis. The results also illustrate the necessity to elaborate this simple hypothesis to account for the roles of adjacent hydrocarbon moieties in defining stability cores of partially folded states along folding reaction coordinates. PMID:26660714
Cross-linking of hen egg white lysozyme by microbial transglutaminase under high hydrostatic pressure: localization of reactive amino acid side chains.
Schuh, Susanne; Schwarzenbolz, Uwe; Henle, Thomas
After incubation of hen egg white lysozyme (HEWL) with microbial transglutaminase (mTG) under high pressure (400-600 MPa for 30 min at 40 °C), the formation of HEWL oligomers was observed via SDS electrophoresis. At atmospheric pressure, HEWL represents no substrate for mTG. Likewise, enzymatic treatment following a pretreatment with high pressure did not lead to oligomerization. Reactive amino acid side chains were identified by peptide mapping after tryptic digestion using RP-HPLC with ESI-TOF-MS. Isopeptide-containing peptide fragments were found only in HEWL samples simultaneously treated with enzyme and pressure. It was found that mTG exclusively cross-links HEWL under high pressure by formation of an isopeptide between lysine at position 1 and glutamine at position 121 in the peptide chain. Therefore, a pressure-induced partial and reversible unfolding of the protein with exposure of lysine and glutamine side chains has to occur, resulting in a site-directed oligomerization of HEWL by mTG. The enzymatic modification of HEWL by mTG under high pressure offers interesting perspectives for further functionalization reactions. PMID:21087031
The characteristics and transfection efficiency of cationic poly (ester-co-urethane) - short chain PEI conjugates self-assembled with DNA.
Liu, Xin-Yi; Ho, Wen-Yueh; Hung, Wei Jing; Shau, Min-Da
To improve the transfection efficiency of polycations with DNA, we synthesized poly(ester-co-urethane)(PEU-g-PEI800) with short chain PEI800 in the side chain, and poly(ester-co-urethane)(PEU) without short chain PEI800. Both PEU-g-PEI800 and PEU, readily self-assembled with plasmid DNA (pCMV-betagal) in a HEPES buffer, were characterized by dynamic light scattering and zeta-potential. The results reveal that PEU-g-PEI800 and PEU were able to self-assemble particles with DNA and yield nano-sized complexes (<200nm) with positive charge at N/P ratios of 20/1 and 120/1, respectively. The degradation studies indicate that the half-life of PEU-g-PEI800 and PEU in the HEPES buffer were 14 and 35h at pH 7.4, respectively. Titration studies were performed to determine the buffering capacities of the polymers. The COS-7 cell viabilities in the presence of PEU-g-PEI800/DNA, PEU/DNA, and PEI25k/DNA were studied. In addition, The PEU-g-PEI800/DNA complexes were able to transfect COS-7 cells in vitro with a high efficiency comparable to a well-known gene carrier PEI25k. The results indicate that PEU-g-PEI800 is an attractive cationic poly (ester-co-urethane) for gene delivery and an interesting candidate for further study. PMID:19775745
Mouse Siglec-1 Mediates trans-Infection of Surface-bound Murine Leukemia Virus in a Sialic Acid N-Acyl Side Chain-dependent Manner.
Erikson, Elina; Wratil, Paul R; Frank, Martin; Ambiel, Ina; Pahnke, Katharina; Pino, Maria; Azadi, Parastoo; Izquierdo-Useros, Nuria; Martinez-Picado, Javier; Meier, Chris; Schnaar, Ronald L; Crocker, Paul R; Reutter, Werner; Keppler, Oliver T
Siglec-1 (sialoadhesin, CD169) is a surface receptor on human cells that mediates trans-enhancement of HIV-1 infection through recognition of sialic acid moieties in virus membrane gangliosides. Here, we demonstrate that mouse Siglec-1, expressed on the surface of primary macrophages in an interferon-α-responsive manner, captures murine leukemia virus (MLV) particles and mediates their transfer to proliferating lymphocytes. The MLV infection of primary B-cells was markedly more efficient than that of primary T-cells. The major structural protein of MLV particles, Gag, frequently co-localized with Siglec-1, and trans-infection, primarily of surface-bound MLV particles, efficiently occurred. To explore the role of sialic acid for MLV trans-infection at a submolecular level, we analyzed the potential of six sialic acid precursor analogs to modulate the sialylated ganglioside-dependent interaction of MLV particles with Siglec-1. Biosynthetically engineered sialic acids were detected in both the glycolipid and glycoprotein fractions of MLV producer cells. MLV released from cells carrying N-acyl-modified sialic acids displayed strikingly different capacities for Siglec-1-mediated capture and trans-infection; N-butanoyl, N-isobutanoyl, N-glycolyl, or N-pentanoyl side chain modifications resulted in up to 92 and 80% reduction of virus particle capture and trans-infection, respectively, whereas N-propanoyl or N-cyclopropylcarbamyl side chains had no effect. In agreement with these functional analyses, molecular modeling indicated reduced binding affinities for non-functional N-acyl modifications. Thus, Siglec-1 is a key receptor for macrophage/lymphocyte trans-infection of surface-bound virions, and the N-acyl side chain of sialic acid is a critical determinant for the Siglec-1/MLV interaction. PMID:26370074
Electroactive polymer-peptide conjugates for adhesive biointerfaces.
Maione, Silvana; Gil, Ana M; Fabregat, Georgina; Del Valle, Luis J; Triguero, Jordi; Laurent, Adele; Jacquemin, Denis; Estrany, Francesc; Jiménez, Ana I; Zanuy, David; Cativiela, Carlos; Alemán, Carlos
Electroactive polymer-peptide conjugates have been synthesized by combining poly(3,4-ethylenedioxythiophene), a polythiophene derivative with outstanding properties, and an Arg-Gly-Asp (RGD)-based peptide in which Gly has been replaced by an exotic amino acid bearing a 3,4-ethylenedioxythiophene ring in the side chain. The incorporation of the peptide at the ends of preformed PEDOT chains has been corroborated by both FTIR and X-ray photoelectron spectroscopy. Although the morphology and topology are not influenced by the incorporation of the peptide at the ends of PEDOT chains, this process largely affects other surface properties. Thus, the wettability of the conjugates is considerably higher than that of PEDOT, independently of the synthetic strategy, whereas the surface roughness only increases when the conjugate is obtained using a competing strategy (i.e. growth of the polymer chains against termination by end capping). The electrochemical activity of the conjugates has been found to be higher than that of PEDOT, evidencing the success of the polymer-peptide links designed by chemical similarity. Density functional theory calculations have been used not only to ascertain the conformational preferences of the peptide but also to interpret the electronic transitions detected by UV-vis spectroscopy. Electroactive surfaces prepared using the conjugates displayed the higher bioactivities in terms of cell adhesion, with the relative viabilities being dependent on the roughness, wettability and electrochemical activity of the conjugate. In addition to the influence of the peptide fragment in the initial cell attachment and subsequent cell spreading and survival, the results indicate that PEDOT promotes the exchange of ions at the conjugate-cell interface. PMID:26372182
Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into β-functionalized α-ketoamides
Huck, Lena; González, Juan F; de la Cuesta, Elena
Summary A sequential three-component process is described, starting from 3-arylmethylene-2,5-piperazinediones and involving a one-pot sequence of reactions achieving regioselective opening of the 2,5-diketopiperazine ring and diastereoselective generation of an aziridine ring. This method allows the preparation of N-unprotected, trisubstituted aziridines bearing a peptide side chain under mild conditions. Their transformation into β-trifluoroacetamido-α-ketoamide and α,β-diketoamide frameworks was also achieved in a single step. PMID:27559422
Molecular structures and antiproliferative activity of side-chain saturated and homologated analogs of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone
NASA Astrophysics Data System (ADS)
Pal, Sanjima; Jadhav, Mahesh; Weyhermüller, Thomas; Patil, Yogesh; Nethaji, M.; Kasabe, Umesh; Kathawate, Laxmi; Konkimalla, V. Badireenath; Salunke-Gawali, Sunita
Side chain homologated derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: pentyl; L-5, hexyl; L-6, heptyl; L-7 and octyl; L-8} have been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-visible spectroscopy and LC-MS. Compounds, L-4, {n-alkyl: butyl; L-4}, L-6 and L-8 have been characterized by single crystal X-ray diffraction studies. The single crystal X-ray structures reveal that L-4 and L-8 crystallizes in P21 space group, while L-6 in P21/c space group. Molecules of L-4 and L-8 from polymeric chains through Csbnd H⋯O and Nsbnd H⋯O close contacts. L-6 is a dimer formed by Nsbnd H⋯O interaction. Slipped π-π stacking interactions are observed between quinonoid and benzenoid rings of L-4 and L-8. Orientations of alkyl group in L-4 and L-8 is on same side of the chain and polymeric chains run opposite to one another to form zip like structure to the alkyl groups. Antiproliferative activities of L-1 to L-8{n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} were studied in cancer cells of colon (COLO205), brain (U87MG) and pancreas (MIAPaCa2) where L-1, L-2 and L-3 were active in MIAPaCa2 (L-1 = L-2 > L-3) and COLO205 (L-2 = L-3 > L-1) and inactive in U87MG. From antiproliferative studies with compounds L-1 to L-8 it can be concluded that homologation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone with saturated methyl groups yielded tissue specific compounds such as L-2 (for MIAPaCa2) and L-3 (for COLO205) with optimal activity.
Physics-based potentials for the coupling between backbone- and side-chain-local conformational states in the united residue (UNRES) force field for protein simulations
Sieradzan, Adam K.; Krupa, Paweł; Scheraga, Harold A.; Liwo, Adam; Czaplewski, Cezary
The UNited RESidue (UNRES) model of polypeptide chains is a coarse-grained model in which each amino-acid residue is reduced to two interaction sites, namely a united peptide group (p) located halfway between the two neighboring α-carbon atoms (Cαs), which serve only as geometrical points, and a united side chain (SC) attached to the respective Cα. Owing to this simplification, millisecond Molecular Dynamics simulations of large systems can be performed. While UNRES predicts overall folds well, it reproduces the details of local chain conformation with lower accuracy. Recently, we implemented new knowledge-based torsional potentials (Krupa et. al. J. Chem. Theory Comput., 2013, 9, 4620–4632) that depend on the virtual-bond dihedral angles involving side chains: Cα ⋯ Cα ⋯ Cα ⋯ SC (τ(1)), SC ⋯ Cα ⋯ Cα ⋯ Cα (τ(2)), and SC ⋯ Cα ⋯ Cα ⋯ SC (τ(3)) in the UNRES force field. These potentials resulted in significant improvement of the simulated structures, especially in the loop regions. In this work, we introduce the physics-based counterparts of these potentials, which we derived from the all-atom energy surfaces of terminally-blocked amino-acid residues by Boltzmann integration over the angles λ(1) and λ(2) for rotation about the Cα ⋯ Cα virtual-bond angles and over the side-chain angles χ. The energy surfaces were, in turn, calculated by using the semiempirical AM1 method of molecular quantum mechanics. Entropy contribution was evaluated with use of the harmonic approximation from Hessian matrices. One-dimensional Fourier series in the respective virtual-bond-dihedral angles were fitted to the calculated potentials, and these expressions have been implemented in the UNRES force field. Basic calibration of the UNRES force field with the new potentials was carried out with eight training proteins, by selecting the optimal weight of the new energy terms and reducing the weight of the regular torsional terms. The force field was
Polymer-drug conjugates for intracellar molecule-targeted photoinduced inactivation of protein and growth inhibition of cancer cells
NASA Astrophysics Data System (ADS)
Wang, Bing; Yuan, Huanxiang; Zhu, Chunlei; Yang, Qiong; Lv, Fengting; Liu, Libing; Wang, Shu
For most molecule-targeted anticancer systems, intracellular protein targets are very difficult to be accessed by antibodies, and also most efforts are made to inhibit protein activity temporarily rather than inactivate them permanently. In this work we firstly designed and synthesized multifunctional polymer-drug conjugates (polythiophene-tamoxifen) for intracellular molecule-targeted binding and inactivation of protein (estrogen receptor α, ERα) for growth inhibition of MCF-7 cancer cells. Small molecule drug was conjugated to polymer side chain for intracellular signal protein targeting, and simultaneously the fluorescent characteristic of polymer for tracing the cellular uptake and localization of polythiophene-drug conjugates by cell imaging. Under light irradiation, the conjugated polymer can sensitize oxygen to produce reactive oxygen species (ROS) that specifically inactivate the targeted protein, and thus inhibit the growth of tumor cells. The conjugates showed selective growth inhibition of ERα positive cancer cells, which exhibits low side effect for our intracellular molecule-targeted therapy system.
Synthesis and Non-Resonant Nonlinear Optical Properties of Push-Pull Side-Chain Azobenzene Polymers
NASA Astrophysics Data System (ADS)
Fedus, K.; Smokal, V.; Krupka, O.; Boudebs, G.
In this work, we report preliminary results obtained for methacrylic polymers incorporating azobenzene side-group as nonlinear optical (NLO) active molecule. The trans-cis isomerization properties are discussed. The third-order non-resonant nonlinear refractive index (n2) and nonlinear absorption coefficient (β) are measured using the Z-scan technique at 1064 nm in the picosecond regime. The influence of different electron-acceptor groups in azobenzene moieties on the nonlinear properties is investigated.
In situ hybridization chain reaction mediated ultrasensitive enzyme-free and conjugation-free electrochemcial genosensor for BRCA-1 gene in complex matrices.
Yang, Hui; Gao, Yang; Wang, Siqi; Qin, You; Xu, Lu; Jin, Dan; Yang, Fan; Zhang, Guo-Jun
In this study, we report an enzyme-free and conjugation-free electrochemical genosensor enabling an ultrasensitive readout of BRCA-1, a breast cancer susceptibility gene. The sensor employs a target-responsive hybridization chain reaction (HCR) to significantly amplify the detectable current signals. By means of a functional auxiliary probe pair and a versatile initiator sequence, a linear DNA concatemer structure can be formed via spontaneous and continuous polymerization of DNA oligomers in the presence of target sequence. Such a DNA nanoassembly endows the genosensor an ultrahigh sensitivity up to 1 aM, which is higher than that of the nanomaterials-based or enzyme mediated amplification approaches by several orders of magnitude. More importantly, the sensor's responsive peak current exhibits a favorable linear correlation to the logarithm of the concentrations of target sequence ranging from 1aM to 10pM. In addition, the sensor is highly selective, and can discriminate a single mismatched sequence. This HCR-based genosensor is also capable of probing low-abundance BRCA-1 gene sequence directly in complex matrices, such as 50% human serum, with minimal interference. These advantages will make our tailor-engineered HCR-based electrochemical genosensor appealing to genetic analysis and clinical diagnostics. PMID:26875018
Polarizabilities of π-Conjugated Chains Revisited: Improved Results from Broken-Symmetry Range-Separated DFT and New CCSD(T) Benchmarks.
Oviedo, M Belén; Ilawe, Niranjan V; Wong, Bryan M
We present a detailed analysis of nonempirically tuned range-separated functionals, with both short- and long-range exchange, for calculating the static linear polarizability and second hyperpolarizabilities of various polydiacetylene (PDA) and polybutatriene (PBT) oligomers. Contrary to previous work on these systems, we find that the inclusion of some amount of short-range exchange does improve the accuracy of the computed polarizabilities and second hyperpolarizabilities. Most importantly, in contrast to prior studies on these oligomers, we find that the lowest-energy electronic states for PBT are not closed-shell singlets, and enhanced accuracy with range-separated DFT can be obtained by allowing the system to relax to a lower-energy broken-symmetry solution. Both the computed polarizabilities and second hyperpolarizabilities for PBT are significantly improved with these broken-symmetry solutions when compared to previously published and current benchmarks. In addition to these new analyses, we provide new large-scale CCSD(T) and explicitly correlated CCSD(T)-F12 benchmarks for the PDA and PBT systems, which comprise the most complete and accurate calculations of linear polarizabilities and second hyperpolarizabilities on these systems to date. These new CCSD(T) and CCSD(T)-F12 benchmarks confirm our DFT results and emphasize the importance of broken-symmetry effects when calculating polarizabilities and hyperpolarizabilties of π-conjugated chains. PMID:27331862
Comparison of Side-Chain Motion of Calbindin D-9k in Its Four Calcium Binding States by Molecular Dynamics Simulation
NASA Astrophysics Data System (ADS)
Thapa, Mahendra; Rance, Mark
Calbindin D-9k,a small single domain protein found predominantly in tissues involved in the uptake and transport of calcium, consists of a single pair of a helix-loop-helix motif (called EF-hand) that binds calcium with the ligands provided by the loop residues and helical residues immediately adjacent to the loop. It exits in four calcium binding states: a doubly loaded state (a state with a calcium atom in each of its two binding sites), two singly loaded states (a state with calcium in its first binding site only and a state with calcium in its second binding site) and an apo-state (a state with no calcium atom). Experiments have shown that calcium binding occurs in a positive cooperative fashion. This fact is also supported by computational studies on dynamics of backbone of the protein.Studies of the methyl side chain dynamics of the doubly loaded state of the protein by molecular dynamics simulation further enhances the point. To further investigate by computation, the molecular dynamics simulation approach has been used to study the side chain dynamics of all four calcium binding states of the protein. In the study, the different kinds of force fields, especially the AMBER (a molecular dynamics simulation suit) force fields, and different kinds of water models are employed in the GPU environment.
Graft copolymer composed of cationic backbone and bottle brush-like side chains as a physically adsorbed coating for protein separation by capillary electrophoresis.
Zhou, Dan; Xiang, Lina; Zeng, Rongju; Cao, Fuhu; Zhu, Xiaoxi; Wang, Yanmei
To stabilize electroosmotic flow (EOF) and suppress protein adsorption onto the silica capillary inner wall, a cationic hydroxyethylcellulose-graft-poly (poly(ethylene glycol) methyl ether methacrylate) (cat-HEC-g-PPEGMA) graft copolymer composed of cationic backbone and bottle brush-like side chains was synthesized for the first time and used as a novel physically adsorbed coating for protein separation by capillary electrophoresis. Reversed (anodal) and very stable EOF was obtained in cat-HEC-g-PPEGMA-coated capillary at pH 2.2-7.8. The effects of degree of cationization, PEGMA grafting ratio, PEGMA molecular mass, and buffer pH on the separation of basic proteins were investigated. A systematic comparative study of protein separation in bare and HEC-coated capillaries and in cat-HEC-g-PPEGMA-coated capillary was also performed. The basic proteins can be well separated in cat-HEC-g-PPEGMA-coated capillary over the pH range of 2.8-6.8 with good repeatability and high separation efficiency, because the coating combines good protein-resistant property of bottle brush-like PPEGMA side chains with excellent coating ability of cat-HEC backbone. Besides its success in separation of basic proteins, the cat-HEC-g-PPEGMA coating was also superior in the fast separation of other protein samples, such as protein mixture, egg white, and saliva, which indicates that it is a promising coating for further proteomics analysis. PMID:22038787
Effects of short-side-chain perfluorosulfonic acid ionomers as binders on the performance of low Pt loading fuel cell cathodes
NASA Astrophysics Data System (ADS)
Park, Young-Chul; Kakinuma, Katsuyoshi; Uchida, Hiroyuki; Watanabe, Masahiro; Uchida, Makoto
We investigated the effects of short-side-chain (SSC) perfluorosulfonic acid ionomers on the electrochemical properties, fuel cell performance and ionomer distribution of a highly dispersed Pt/GCB catalyst with a low Pt loading, 0.05 mg cm-2. The SSC ionomers in the cathode catalyst layers (CLs) resulted in an improvement of the Pt utilization (UPt) and Pt effectiveness (EfPt) values compared with those for the conventional long-side-chain (LSC) ionomer. Furthermore, the SSC ionomers with high ion exchange capacity (IEC), e.g., SSC-1.43 and SSC-1.80 ionomers, exhibited significantly enhanced cell performance under low to medium relative humidity (RH) conditions. This result is ascribed to the higher proton conductivity of the SSC ionomers and more effective trapping of water that is produced during the oxygen reduction reaction (ORR) than those of the LSC ionomer. It was also found that the SSC ionomers showed better continuity and uniformity on the Pt and carbon particles than the LSC ionomer, which might have led to improvement of both the mass transport and the proton-conducting network in the CLs. The application of the SSC ionomers as binders demonstrated an increase of the performance at the low Pt loading fuel cell cathode over a wide range of humidity.
Stimulation of cholesterol side-chain cleavage by a luteinizing-hormone-releasing hormone (luliberin) agonist (ICI 118630) in rat Leydig cells.
Sullivan, M H; Cooke, B A
The action of a luliberin (luteinizing-hormone-releasing hormone) agonist (ICI 118630) and lutropin (luteinizing hormone) on the activity of the cytochrome P-450 cholesterol side-chain cleavage enzyme in rat Leydig cells has been investigated. This has been carried out by studying the metabolism of exogenous (22R)-22- and 25-hydroxycholesterol to testosterone. It was found that both hydroxycholesterols increased testosterone production to higher levels than achieved by lutropin alone. Addition of luliberin agonist but not lutropin was found to increase further the metabolism of the hydroxycholesterol to testosterone; this occurred in the presence of saturating and subsaturating levels of the hydroxycholesterols. This effect of luliberin agonist was potentiated in the presence of lutropin. The protein synthesis inhibitor, cycloheximide, inhibited the luliberin agonist-induced stimulation of the hydroxycholesterol metabolism. At low calcium levels (1.1 microM), testosterone production was increased by addition of (22R)-22-hydroxycholesterol but the luliberin agonist effect was negated. The calmodulin inhibitor trifluoperazine inhibited (22R)-22-hydroxycholesterol-stimulated steroidogenesis and negated the luliberin agonist effect. These results indicate that luliberin agonist specifically increases the synthesis of the cytochrome P-450 cholesterol side-chain cleavage enzyme in rat testis Leydig cells. PMID:6230077
Characterization of conformational exchange of a histidine side chain: protonation, rotamerization, and tautomerization of His61 in plastocyanin from Anabaena variabilis.
Hass, Mathias A S; Hansen, D Flemming; Christensen, Hans E M; Led, Jens J; Kay, Lewis E
A model describing conformational exchange of His 61 in plastocyanin from Anabaena variabilis is presented. A detailed picture of the exchange dynamics has been obtained using solution NMR relaxation measurements, chemical shift titrations, and structural information provided by a high-resolution crystal structure of the protein. A three-site model for chemical exchange that involves interconversion among the tautomeric and protonated forms of the histidine side chain with rates that are fast on the NMR chemical shift time scale can account for all of the data. In general, in the limit of fast exchange, it is not possible to obtain separate measures of chemical shift differences and populations of the participating states using NMR. However, we show here that when the data mentioned above are combined, it is possible to extract values of all of the parameters that characterize the exchange process, including rates, populations, and chemical shift changes, and to provide cross-validations that establish their accuracy. The methodology is generally applicable to the study of histidine side chain dynamics, which can play an important functional role in many protein systems. PMID:18540585
Introduction of a methoxymethyl side chain into p-phenylenediamine attenuates its sensitizing potency and reduces the risk of allergy induction
Goebel, Carsten; Troutman, John; Hennen, Jenny; Rothe, Helga; Schlatter, Harald; Gerberick, G. Frank; Blömeke, Brunhilde
The strong sensitizing potencies of the most important primary intermediates of oxidative hair dyes, p-phenylenediamine (PPD) and p-toluylenediamine (PTD, i.e. 2-methyl-PPD) are well established. They are considered as the key sensitizers in hair dye allergic contact dermatitis. While modification of their molecular structure is expected to alter their sensitizing properties, it may also impair their color performance. With introduction of a methoxymethyl side chain we found the primary intermediate 2-methoxymethyl-p-phenylenediamine (ME-PPD) with excellent hair coloring performance but significantly reduced sensitizing properties compared to PPD and PTD: In vitro, ME-PPD showed an attenuated innate immune response when analyzed for its protein reactivity and dendritic cell activation potential. In vivo, the effective concentration of ME-PPD necessary to induce an immune response 3-fold above vehicle control (EC3 value) in the local lymph node assay (LLNA) was 4.3%, indicating a moderate skin sensitizing potency compared to values of 0.1 and 0.17% for PPD and PTD, respectively. Finally, assessing the skin sensitizing potency of ME-PPD under consumer hair dye usage conditions through a quantitative risk assessment (QRA) indicated an allergy induction risk negligible compared to PPD or PTD. - Highlights: • Methoxymethyl side chain in p-phenylenediamine reduces its strong skin sensitizing properties. • Reduced protein reactivity and dendritic cell activation. • Reduced skin sensitizing potency in local lymph node assay (LLNA). • Negligible allergy induction risk under hair dye usage conditions.
Side-chain-to-tail cyclization of ribosomally derived peptides promoted by aryl and alkyl amino-functionalized unnatural amino acids.
Frost, John R; Wu, Zhijie; Lam, Yick Chong; Owens, Andrew E; Fasan, Rudi
A strategy for the production of side-chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Two genetically encodable unnatural amino acids, bearing either an aryl or alkyl amino group, were investigated for their efficiency toward promoting the formation of medium to large-sized peptide macrocycles via intein-mediated side-chain-to-C-terminus cyclization. While only partial cyclization was observed with precursor proteins containing para-amino-phenylalanine, efficient peptide macrocyclization could be achieved using O-2-aminoethyl-tyrosine as the reactive moiety. Conveniently, the latter was generated upon quantitative, post-translational reduction of the azido-containing counterpart, O-2-azidoethyl-tyrosine, directly in E. coli cells. This methodology could be successfully applied for the production of a 12 mer cyclic peptide with enhanced binding affinity for the model target protein streptavidin as compared to the acyclic counterpart (KD: 5.1 μM vs. 22.4 μM), thus demonstrating its utility toward the creation and investigation of novel, functional macrocyclic peptides. PMID:27064594
Gauche(+) side-chain orientation as a key factor in the search for an immunogenic peptide mixture leading to a complete fully protective vaccine.
Bermúdez, Adriana; Calderon, Dayana; Moreno-Vranich, Armando; Almonacid, Hannia; Patarroyo, Manuel A; Poloche, Andrés; Patarroyo, Manuel E
Topological and stereo-electron characteristics are essential in major histocompability class II-peptide-T-cell receptor (MHC-p-TCR) complex formation for inducing an appropriate immune response. Modified high activity binding peptides (mHABPs) were synthesised for complete full protection antimalarial vaccine development producing a large panel of individually fully protection-inducing protein structures (FPIPS) and very high long-lasting antibody-inducing (VHLLAI) mHABPs. Most of those which did not interfere, compete, inhibit or suppress their individual VHLLAI or FPIPS activity contained or displayed a polyproline II-like (PPIIL) structure when mixed. Here we show that amino acid side-chains located in peptide binding region (PBR) positions p3 and p7 displayed specific electron charges and side-chain gauche(+) orientation for interacting with the TCR. Based on the above, and previously described physicochemical principles, non-interfering, long-lasting, full protection-inducing, multi-epitope, multistage, minimal subunit-based chemically synthesised mHABP mixtures can be designed for developing vaccines against diseases scourging humankind, malaria being one of them. PMID:24582630
Structure-activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure 4: Role of acyl side chains on d-mannose.
Tsutsui, Nozomi; Tanabe, Genzoh; Ikeda, Nami; Okamura, Saika; Ogawa, Marika; Miyazaki, Kuniko; Kita, Ayako; Sugiura, Reiko; Muraoka, Osamu
As part of an ongoing study on the structure-activity relationship of acremomannolipin A (1)-the novel glycolipid isolated from Acremonium strictum possessing potent calcium signal-modulating activity-the role of acyl substituents on the d-mannose moiety was examined. Three partially deacylated homologs (2a-2c) and 20 homologs (2d-2w) bearing different acyloxy side chains were synthesized via the stereoselective β-mannosylation of appropriately protected mannosyl sulfoxides (3) with d-mannitol derivatives (4), and their calcium signal-modulating activities were examined. The activities of 2a-2c were completely lost. Homologs bearing relatively short acyloxy groups at C-3, C-4, and C-6 positions (2t-2v) exhibited less activity than 1, whereas a heptanoyl homolog (2w: C7) maintained activity nearly equal to that of 1. When the acyl groups at these three positions were substituted by an octanoyl group (2i: C8), the activity was completely lost. On the other hand, of the 10 homologs in which the octanoyl at C-2 was substituted by other acyloxy moieties (2j-2s), three (2m: C7, 2n: C9, 2o: C10) maintained potent activity. These results suggested that peracylated mannose structure is critical for calcium signal-modulating activity, and this activity is precisely dependent on the length of four acyl side chains on d-mannose. PMID:27243802
Block Copolymer Micelles with Acid-labile Ortho Ester Side-chains: Synthesis, Characterization, and Enhanced Drug Delivery to Human Glioma Cells
Tang, Rupei; Ji, Weihang; Panus, David; Palumbo, R. Noelle; Wang, Chun
A new type of block copolymer micelles for pH-triggered delivery of poorly water-soluble anticancer drugs has been synthesized and characterized. The micelles were formed by the self-assembly of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic polymethacrylate block (PEYM) bearing acid-labile ortho ester side-chains. The diblock copolymer was synthesized by atom transfer radical polymerization (ATRP) from a PEG macro-initiator to obtain well-defined polymer chain-length. The PEG-b-PEYM micelles assumed a stable core-shell structure in aqueous buffer at physiological pH with a low critical micelle concentration as determined by proton NMR and pyrene fluorescence spectroscopy. The hydrolysis of the ortho ester side-chain at physiological pH was minimal yet much accelerated at mildly acidic pHs. Doxorubicin (Dox) was successfully loaded into the micelles at pH 7.4 and was released at much higher rate in response to slight acidification to pH 5. Interestingly, the release of Dox at pH 5 followed apparently a biphasic profile, consisting of an initial fast phase of several hours followed by a sustained release period of several days. Dox loaded in the micelles was rapidly taken up by human glioma (T98G) cells in vitro, accumulating in the endolysosome and subsequently in the nucleus in a few hours, in contrast to the very low uptake of free drug at the same dose. The dose-dependent cytotoxicity of the Dox-loaded micelles was determined by the MTT assay and compared with that of the free Dox. While the empty micelles themselves were not toxic, the IC50 values of the Dox-loaded micelles were approximately ten-times (by 24 hours) and three-times (by 48 hours) lower than the free drug. The much enhanced potency in killing the multi-drug-resistant human glioma cells by Dox loaded in the micelles could be attributed to high intracellular drug concentration and the subsequent pH-triggered drug release. These
Preparation of thermocleavable conjugates based on ansamitocin and superparamagnetic nanostructured particles by a chemobiosynthetic approach.
Mancuso, Lena; Knobloch, Tobias; Buchholz, Jessica; Hartwig, Jan; Möller, Lena; Seidel, Katja; Collisi, Wera; Sasse, Florenz; Kirschning, Andreas
A combination of mutasynthesis, precursor-directed biosynthesis and semisynthesis provides access to new ansamitocin derivatives including new nanostructured particle-drug conjugates. These conjugates are based on the toxin ansamitocin and superparamagnetic iron oxide-silica core shell particles. New ansamitocin derivatives that are functionalized either with alkynyl- or azido groups in the ester side chain at C-3 are attached to nanostructured iron oxide core-silica shell particles. Upon exposure to an oscillating electromagnetic field these conjugates heat up and the ansamitocin derivatives are released by a retro-Diels-Alder reaction. For example, one ansamitocin derivative exerts strong antiproliferative activity against various cancer cell lines in the lower nanomolar range while the corresponding nanostructured particle-drug conjugate is not toxic. Therefore, these new conjugates can serve as dormant toxins that can be employed simultaneously in hyperthermia and chemotherapy when external inductive heating is applied. PMID:25346489
Controlling molecular ordering in solution-state conjugated polymers
NASA Astrophysics Data System (ADS)
Zhu, J.; Han, Y.; Kumar, R.; He, Y.; Hong, K.; Bonnesen, P. V.; Sumpter, B. G.; Smith, S. C.; Smith, G. S.; Ivanov, I. N.; Do, C.
Rationally encoding molecular interactions that can control the assembly structure and functional expression in a solution of conjugated polymers hold great potential for enabling optimal organic optoelectronic and sensory materials. In this work, we show that thermally-controlled and surfactant-guided assembly of water-soluble conjugated polymers in aqueous solution is a simple and effective strategy to generate optoelectronic materials with the desired molecular ordering. We have studied a conjugated polymer consisting of a hydrophobic thiophene backbone and hydrophilic, thermo-responsive ethylene oxide side groups, which shows a step-wise, multi-dimensional assembly in water. By incorporating the polymer into phase-segregated domains of an amphiphilic surfactant in solution, we demonstrate that both chain conformation and degree of molecular ordering of the conjugated polymer can be tuned in hexagonal, micellar and lamellar phases of the surfactant solution. The controlled molecular ordering in conjugated polymer assembly is demonstrated as a key factor determining the electronic interaction and optical function.Rationally encoding molecular interactions that can control the assembly structure and functional expression in a solution of conjugated polymers hold great potential for enabling optimal organic optoelectronic and sensory materials. In this work, we show that thermally-controlled and surfactant-guided assembly of water-soluble conjugated polymers in aqueous solution is a simple and effective strategy to generate optoelectronic materials with the desired molecular ordering. We have studied a conjugated polymer consisting of a hydrophobic thiophene backbone and hydrophilic, thermo-responsive ethylene oxide side groups, which shows a step-wise, multi-dimensional assembly in water. By incorporating the polymer into phase-segregated domains of an amphiphilic surfactant in solution, we demonstrate that both chain conformation and degree of molecular ordering
Composition of the epicuticular waxes coating the adaxial side of Phyllostachys aurea leaves: Identification of very-long-chain primary amides.
Racovita, Radu C; Jetter, Reinhard
The present study presents comprehensive chemical analyses of cuticular wax mixtures of the bamboo Phyllostachys aurea. The epicuticular and intracuticular waxes were sampled selectively from the adaxial side of leaves on young and old plants and investigated by gas chromatography-mass spectrometry and flame ionization detection. The epi- and intracuticular layers on young and old leaves had wax loads ranging from 1.7 μg/cm(2) to 1.9 μg/cm(2). Typical very-long-chain aliphatic wax constituents were found with characteristic chain length patterns, including alkyl esters (primarily C48), alkanes (primarily C29), fatty acids (primarily C28 and C16), primary alcohols (primarily C28) and aldehydes (primarily C30). Alicyclic wax components were identified as tocopherols and triterpenoids, including substantial amounts of triterpenoid esters. Alkyl esters, alkanes, fatty acids and aldehydes were found in greater amounts in the epicuticular layer, while primary alcohols and most terpenoids accumulated more in the intracuticular wax. Alkyl esters occurred as mixtures of metamers, combining C20 alcohol with various acids into shorter ester homologs (C36C40), and a wide range of alcohols with C22 and C24 acids into longer esters (C42C52). Primary amides were identified, with a characteristic chain length profile peaking at C30. The amides were present exclusively in the epicuticular layer and thus at or near the surface, where they may affect plant-herbivore or plant-pathogen interactions. PMID:27402630
Optimal design of ethanol supply chains considering carbon trading effects and multiple technologies for side-product exploitation.
Ortiz-Gutiérrez, R A; Giarola, S; Bezzo, F
This work proposes a spatially explicit mixed integer linear programming modelling framework representing the dynamic evolution of a bioethanol supply chain (SC) under increasing biofuel demand and greenhouse gas (GHG) emission savings over time. Key features of the proposed framework comprise: (i) the incorporation of available set-aside rural surfaces for energy crop cultivation; (ii) the acknowledgement ofan economic value to the overall GHG emissions through the introduction of an Emission Trading System. Multiple technological options are assessed to exploit the co-product Distiller's Dried Grains with Solubles either as animal fodder (standard usage) or as fuel for heat and power generation or as raw material for biogas production (and hence heat and power). Bioethanol production in Northern Italy is chosen as a demonstrative case study. PMID:24350473
Side-chain effects on the solution-phase conformations and charge photogeneration dynamics of low-bandgap copolymers
NASA Astrophysics Data System (ADS)
Huo, Ming-Ming; Liang, Ran; Xing, Ya-Dong; Hu, Rong; Zhao, Ning-Jiu; Zhang, Wei; Fu, Li-Min; Ai, Xi-Cheng; Zhang, Jian-Ping; Hou, Jian-Hui
Solution-phase conformations and charge photogeneration dynamics of a pair of low-bandgap copolymers based on benzo[1,2-b:4,5-b']dithiophene (BDT) and thieno[3,4-b]thiophene (TT), differed by the respective carbonyl (-C) and ester (-E) substituents at the TT units, were comparatively investigated by using near-infrared time-resolved absorption (TA) spectroscopy at 25 °C and 120 °C. Steady-state and TA spectroscopic results corroborated by quantum chemical analyses prove that both PBDTTT-C and PBDTTT-E in chlorobenzene solutions are self-aggregated; however, the former bears a relatively higher packing order. Specifically, PBDTTT-C aggregates with more π-π stacked domains, whereas PBDTTT-E does with more random coils interacting strongly at the chain intersections. At 25 °C, the copolymers exhibit comparable exciton lifetimes (˜1 ns) and fluorescence quantum yields (˜2%), but distinctly different charge photogeneration dynamics: PBDTTT-C on photoexcitation gives rise to a branching ratio of charge separated (CS) over charge transfer (CT) states more than 20% higher than PBDTTT-E does, correlating with their photovoltaic performance. Temperature and excitation-wavelength dependent exciton/charge dynamics suggest that the CT states localize at the chain intersections that are survivable up to 120 °C, and that the excitons and the CS states inhabit the stretched strands and the also thermally robust orderly stacked domains. The stable self-aggregation structures and the associated primary charge dynamics of the PBDTTT copolymers in solutions are suggested to impact intimately on the morphologies and the charge photogeneration efficiency of the solid-state photoactive layers.
Synthesis of dendrigraft poly(ϵ-caprolactone)s using side hydroxyl groups for the grafting of branch chains.
Cheng, Juan; Ling, Xiujun; Zhong, Zhenlin; Zhuo, Renxi
Dendrigraft poly(ϵ-caprolactone)s with high molecular weight and narrow polydispersity are synthesized via a convenient generation-growth approach. Copolymerization of ϵ-caprolactone (CL) and 4-(2-benzoxyethoxy)-ϵ-caprolactone (BECL) with stannous octanoate as a catalyst affords a functionalized poly(ϵ-caprolactone) (PCL) with benzyl-protected hydroxyl side groups. After removal of benzyl groups by palladium-catalyzed hydrogenolysis, the graft copolymerization of CL and BECL onto the hydroxyl-bearing linear polyester (zero-generation) affords the first-generation graft polyester. Further deprotection and graft polymerization cycles led to dendrigraft polyesters. Molecular weights are multiplied in each graft copolymerization. The second-generation dendrigraft poly(ϵ-caprolactone) has an M(w) of 236 000 g·mol(-1) and M(w) /M(n) of 1.53. PMID:21928304
Relationship between lipophilicity and inhibitory activity against cancer cell growth of nine kinds of alk(en)yl trisulfides with different side chains.
Iitsuka, Yuji; Tanaka, Yuki; Hosono-Fukao, Tomomi; Hosono, Takashi; Seki, Taiichiro; Ariga, Toyohiko
Of the compounds contained in or derived from garlic (Allium sativum L.), alk(en)yl sulfides are known to be responsible for most of the physiological or neutraceutical functions of garlic. We previously found that diallyl trisulfide (DATS) is a potent inhibitor of tubulin polymerization and cancer cell growth, and an effective stimulator of the hepatic detoxification system. Here, we synthesized nine trisulfides having different aliphatic side chains, and determined their log P, a parameter for lipophilicity of nonionized solutes, and inhibitory activities, IC50 (microM), toward cancer cell growth. The log P values of these trisulfides ranged from the lowest, 2.72, for dimethyl trisulfide, to the highest, 7.62, for dipentyl trisulfide. The relationship between the IC50 and log P of the nine trisulfides was parabolic in nature, in which dibutenyl- and dipropyl-compounds, determined to have a log P of approximately 5, were located at the minimum point of the parabola, indicating the maximum potency. The reason why DATS, having a log P of about 4, was excessively stronger than diethyl trisulfide, with a similar log P, is not fully understood; but perhaps it can be explained by a higher reactivity of the diallyl compound in nucleophilic substitution. The compounds with 3-carbon chains were stronger in terms of growth inhibition than the others; but weaker compounds, those with 4- or 5-carbon chains, showed higher activity if a double bond was introduced into them to reduce their log P to the effective range. In this study, we confirmed the superiority of trisulfides with 3-carbon chains [i.e., DATS and dipropyl trisulfide (DPTS)]. In addition, we observed for the first time that dibutenyl trisulfide, a compound not found in garlic, is one of the potent structures among alk(en)yl trisulfides. PMID:20939433
Design and synthesis of side-chain conformationally restricted phenylalanines and their use for structure-activity studies on tachykinin NK-1 receptor.
Josien, H; Lavielle, S; Brunissen, A; Saffroy, M; Torrens, Y; Beaujouan, J C; Glowinski, J; Chassaing, G
Constrained analogues of phenylalanine have been conceptually designed for analyzing the binding pockets of Phe7 (S7) and Phe8 (S8), two aromatic residues important for the pharmacological properties of SP, i.e., L-tetrahydroisoquinoleic acid, L-diphenylalanine, L-9-fluorenylglycine (Flg), 2-indanylglycine, the diastereomers of L-1-indanylglycine (Ing) and L-1-benz[f]indanylglycine (Bfi), and the Z and E isomers of dehydrophenylalanine (delta ZPhe, delta EPhe). Binding studies were performed with appropriate ligands and tissue preparations allowing the discrimination of the three tachykinin binding sites, NK-1, NK-2, and NK-3. The potencies of these agonists were evaluated in the guinea pig ileum bioassay. According to the binding data, we can conclude that the S7 subsite is small, only the gauche (-) probe [(2S,3S)-Ing7]SP presents a high affinity for specific NK-1 binding sites. Surprisingly, the [delta EPhe7]SP analogue, which projects the aromatic ring toward the trans orientation, is over 40-fold more potent than the Z isomer, [delta ZPhe7]SP. A plausible explanation of these conflictual results is that either the binding protein quenches the minor trans rotamer of [(2S,3S)-Ing7]SP in solution or this constrained amino acid side chain rotates when inserted in the protein. In position 8, the high binding affinities of [Flg8]SP and [(2S,3S)-Bfi8]SP suggest that the S8 subsite is large enough to accept two aromatic rings in the gauche (-) and one aromatic ring in the trans direction. Peptides bearing two conformational probes in positions 7, 8, or 9 led to postulate that S7, S8, and S9 subsites are independent from each other. The volumes available for side chains 7 and 8 can be estimated to be close to 110 and 240 A3, respectively. The large volume of the S8 subsite raises question on the localization of the SP-binding site in the NK-1 receptor. If SP were to bind in the transmembrane domains, the cleft defined by the seven transmembrane segments must rearrange
Synthesis of novel polymethacrylates with siloxyl bridging perfluoroalkyl side-chains for hydrophobic application on cotton fabrics
NASA Astrophysics Data System (ADS)
Cai, Lu; Dai, Li; Yuan, Yanhua; Liu, Anqi; Zhanxiong, Li
Three novel fluorinated methacrylate monomers with siloxyl bridging perfluoroalkyl groups were synthesized and characterized. Afterwards, the corresponding polymethacrylate latexes, namely monofluoroalkylsiloxyl polymethacrylate (PMFSMA), bisfluoroalkylsiloxyl polymethacrylate (PBFSMA) and trisfluoroalkylsiloxyl polymethacrylate (PTFSMA), were prepared and coated onto cotton fabrics to make them water-repellent. Particle size, particle size distribution, zeta potential and high-resolution transmission electron microscope (TEM) were tested to assess the emulsion stability and particle morphology. Thermal properties of PTFSMA were evaluated by thermal-gravimetric analysis (TGA). Surface properties of the coated cotton fabrics were characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), water contact angle (WCA), adhesive force and X-ray photoelectron spectroscopy (XPS). It was found that the incorporation of more perfluoroalkyl chains and the annealing process could decrease the surface free energy of polymer film to 13.7 mN/m. Furthermore, the EDS spectra of PTFSMA film after annealing showed an enrichment of fluorine in the film-air interface.
Side-chain effect on Langmuir and Langmuir-Blodgett film properties of poly(N-alkylmethacrylamide)-coated magnetic nanoparticle.
Parvin, Salina; Matsui, Jun; Sato, Eriko; Miyashita, Tokuji
We report the fabrication of a Langmuir-Blodgett (LB) film of magnetic nanoparticles (iron oxide) coated by poly(N-alkylmethacrylamide)s with various alkyl chain lengths. The iron oxide nanoparticle (nP) was first modified with a reactive polymer, poly(N-hydroxysuccinimide methacrylate) (pSucMA) by applying surface initiated atom transfer radical polymerization (ATRP) technique. Then the succinimide group was replaced by various amine derivatives. The monolayer behaviors of the resultant nanoparticles, as modified by various poly(N-alkylmethacrylamide)s, such as poly(octylmethacrylamide) (pOMA), poly(dodecylmethacrylamide) (pDDMA), polytetradecylmethacrylamide (pTDMA), and poly(hexadecylmethacrylamide) (pHDMA) were elucidated using surface pressure-area isotherm measurements. Results show that pTDMA-modified nanoparticles (nP-pTDMA) exhibit the highest collapse pressure with a steeply rising surface pressure. The monolayer of nP-pTDMA on the water surface was transferred onto a solid substrate using the LB technique. Atomic force microscopy (AFM) images of the transferred LB film show that nP-pTDMA particles form a uniform nanoparticle monolayer. The LB film of nP-pTDMA with multilayers was fabricated through sequential transfer of the particles monolayer onto the substrate surface. The resultant LB film of nanoparticles shows a superparamagnetic behavior at room temperature. PMID:17511997
The influence of novel gemini surfactants containing cycloalkyl side-chains on the structural phases of DNA in solution.
Pietralik, Zuzanna; Kumita, Janet R; Dobson, Christopher M; Kozak, Maciej
Very important to gene therapy is the delivery system of the nucleic acids (called a vector), which will enhance the efficiency of the transport of new DNA into cells whilst protecting against damage. A promising alternative to the currently used viral vectors are the systems based on amphiphilic compounds - lipoplexes. Among them, gemini surfactants, which consist of two hydrophobic chains and two cationic heads connected by a linker - spacer group, appear to be promising candidates. The subject of this study involves two gemini surfactants, alkoxy derivatives of bis-imidazolium quaternary salts, differing in the length of their spacer groups and how they interact with two types of salmon sperm DNA (low and high molecular weight (MW)) or plasmid DNA (pDNA). The mixtures of gemini surfactants with nucleic acids of differing p/n ratios (positive-to-negative charge ratio) were characterised by small angle X-ray scattering (SAXS) of synchrotron radiation, dynamic light scattering (DLS), circular dichroism (CD) spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM) and gel electrophoresis techniques. This analysis allows for the selection of the most suitable and promising candidates for non-viral vectors in gene therapy, determination of the conditions needed to form stable complexes, identification of conformational changes in the DNA molecules upon interactions with gemini surfactants and in some cases, determination of the structures formed in these lipoplexes. PMID:25969417
Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial.
Breuer, R I; Soergel, K H; Lashner, B A; Christ, M L; Hanauer, S B; Vanagunas, A; Harig, J M; Keshavarzian, A; Robinson, M; Sellin, J H; Weinberg, D; Vidican, D E; Flemal, K L; Rademaker, A W
BACKGROUND: Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. AIMS: To assess the efficacy of topical SCFA treatment in ulcerative colitis. PATIENTS AND METHODS: 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. RESULTS: Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (< 6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p < 0.02) in their clinical and histological activity scores. CONCLUSIONS: Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit. PMID:9176076
Organotitanium(IV) compounds as catalysts for the polymerization of isocyanates: The polymerization of isocyanates with functionalized side chains
Patten, T.E.; Novak, B.M. Lawrence Berkeley Lab., CA )
Catalysts of the form CpTiCl[sub 2]X, where X = [minus]OCH[sub 2]CF[sub 3], [minus]N(CH[sub 3])[sub 2], or [minus]CH[sub 3] (2a, 2b, 2c; Cp = [eta][sup 5]-cyclopentadienyl), CP*TiCl[sub 2]OCH[sub 2]CF[sub 3](3; Cp* = [eta][sup 5]-pentamethylcyclopentadienyl), and Cp[sub 2]TiClOCH[sub 2]-CF[sub 3](4) were used to polymerize a variety of isocyanates. Titanium-alkoxide, -amide, and -alkyl bonds were all found to be active in initiating the insertion of isocyanate monomer. An advantageous consequence of the lesser Lewis acidity of 2a-c relative to TiCl[sub 3]OCH[sub 2]CF[sub 3](1) is that the polymerization of highly functionalized monomers is possible using 2a-c and not 1. 2-Isocyanotoethyl methacrylate (2IEM) was polymerized, using 2b, through the isocyanato group to a linear polymer; the resulting properties of this material were found to be quite different from what was reported by Graham et al. 2IEM trimer was synthesized and subsequently cross-linked using a free-radical initiator, and it was found that the properties of this material matched those of the earlier report. The Diels-Alder adduct of 2IEM with cyclopentadiene, 2-((2-isocyanatoethoxy)carbonyl)-2-methylbicyclo[2.2.1]hept-5-ene (2IECMBH) was prepared and also polymerized using 2b. The use of cyclopentadienyltitanium trichloride derivatives also provides a general route through which a wide variety of end groups may be incorporated onto the end of the polyisocyanate chain.
Architectures for controlling solid state properties of conjugated polymers
NASA Astrophysics Data System (ADS)
Nambiar, Rakesh R.
Conjugated polymers and oligomers are great materials for use in the next generation devices namely organic field effect transistors, light emitting diodes and polymeric solar cells. Apart from having the potential for developing power-efficient, flexible, robust and inexpensive devices, conjugated polymers can also be tuned by molecular design to optimize device characteristics. One key problem for the full commercial exploitation of conjugated polymers is that the charge carrier mobility of the state-of-the-art polymer semiconductors is much lower than required for many applications. The performance of the devices is strongly dependent on the molecular structure and supermolecular assembly of the conjugated polymer chains. This thesis covers our attempts to design molecular structure to control and improve the solid state properties of conjugated polymers. The relative placement of side chains along the backbone has a great influence on the solid state ordering of conjugated polymers. Poly(2,5-disubstituted-1,4-phenylene ethynylene)s (PPE)s, an important class of conjugated polymers, are generally synthesized by Pd-catalyzed coupling polymerizations of appropriately substituted diiodo and diethynyl benzenes (i.e., A-A and B-B type monomers). In asymmetrically substituted PPEs, this results in an irregular substitution pattern of the side chains along the polymer backbone. We report a new synthetic approach to prepare regioregular unsymmetrically substituted PPEs by polymerization of 4-iodophenylacetylenes (i.e., A-B type monomer). We provide a detailed discussion of various approaches to the synthesis of PPEs with different regioregularities and provide a description of the differences between regioregular and regiorandom analogs. The effect of regioregularity becomes even more important when the two side chains are very dissimilar or amphiphilic. We explore the effect of relative placement hydrophobic (dodecyloxy)/hydrophilic (tri(ethylene glycol) and
Incorporation of an Intramolecular Hydrogen-bonding Motif in the Side-Chain of 4-Aminoquinolines Enhances Activity against Drug-Resistant P. falciparum
Madrid, Peter B.; Liou, Ally P.; DeRisi, Joseph L.; Guy, R. Kiplin
Previous data showing that several chloroquine analogs containing an intramolecular hydrogen bonding motif were potent against multidrug-resistant P. falciparum, led to the exploration of the importance of this motif. A series of 116 compounds containing four different alkyl linkers and various aromatic substitutions with hydrogen bond accepting capability was synthesized. The series showed broad potency against the drug-resistant W2 strain of P. falciparum. In particular, a novel series containing variations of the α-aminocresol motif gave 8 compounds with IC50's more potent than 5 nM against the W2 strain. Such simple modifications, significantly altering the pKa and sterics of the basic side chain in chloroquine analogs, may prove to be part of a strategy for overcoming the problem of worldwide resistance to affordable antimalarial drugs. PMID:16854059
Benzyloxycarbonyl-D-Phe-Pro-methoxypropylboroglycine: a novel inhibitor of thrombin with high selectivity containing a neutral side chain at the P1 position.
Claeson, G; Philipp, M; Agner, E; Scully, M F; Metternich, R; Kakkar, V V; DeSoyza, T; Niu, L H
Thrombin, the blood-clotting enzyme, is a serine proteinase with trypsin-like specificity and is able to cleave Arg-Xaa peptide bonds but only in a very limited number of substrates (and sites therein). For the prevention and treatment of thrombosis the control of thrombin activity is a key target, and a variety of synthetic inhibitors have been introduced recently, all of which have a positive charge at the P1 site. We report the synthesis of the first example of a new class of inhibitor containing a neutral side chain at the P1 site, the peptide benzyloxycarbonyl-D-Phe-Pro- methoxypropylboroglycine. The peptide is a potent inhibitor of thrombin [Ki (limiting) = 7 nM] and is highly selective for its target enzyme in respect of other serine proteinases. This may be expected to confer considerable advantage in terms of specificity of action and reduced toxicity over conventional, positively charged, inhibitors. PMID:8452516
Transient and stationary flow behaviour of side chain liquid-crystalline polymers: Evidence of a shear-induced isotropic-to-nematic phase transition
NASA Astrophysics Data System (ADS)
Pujolle-Robic, C.; Olmsted, P. D.; Noirez, L.
This letter describes the non-linear rheology of the isotropic phase of a thermotropic side chain liquid-crystal polymer (SCLCP), from which we infer a flow-induced iso- tropic-to-nematic (IN) phase transition above a critical shear stress and construct non-equilib- rium phase diagrams. In contrast to the well-studied wormlike-micellar solutions and predictions for simple liquid-crystalline systems, the critical stress does not vanish as the equilibrium transition temperature is approached from the above. We postulate that this is due to: i) the coupling between mesogens and the polymer backbone, whose equilibrium oblate nematic backbone conformation contrasts with the prolate non-equilibrium conformation; and ii) the peculiar topological constraints in SCLCP melts, which have been previously postulated as leading to long-lived clusters.
Analyzing sites of OH radical attack (ring vs. side chain) in oxidation of substituted benzenes via dual stable isotope analysis (δ(13)C and δ(2)H).
Zhang, Ning; Geronimo, Inacrist; Paneth, Piotr; Schindelka, Janine; Schaefer, Thomas; Herrmann, Hartmut; Vogt, Carsten; Richnow, Hans H
OH radicals generated by the photolysis of H2O2 can degrade aromatic contaminants by either attacking the aromatic ring to form phenolic products or oxidizing the substituent. We characterized these competing pathways by analyzing the carbon and hydrogen isotope fractionation (εC and εH) of various substituted benzenes. For benzene and halobenzenes that only undergo ring addition, low values of εC (-0.7‰ to -1.0‰) were observed compared with theoretical values (-7.2‰ to -8‰), possibly owing to masking effect caused by pre-equilibrium between the substrate and OH radical preceding the rate-limiting step. In contrast, the addition of OH radicals to nitrobenzene ring showed a higher εC (-3.9‰), probably due to the lower reactivity. Xylene isomers, anisole, aniline, N,N-dimethylaniline, and benzonitrile yielded normal εH values (-2.8‰ to -29‰) indicating the occurrence of side-chain reactions, in contrast to the inverse εH (11.7‰ to 30‰) observed for ring addition due to an sp(2) to sp(3) hybridization change at the reacting carbon. Inverse εH values for toluene (14‰) and ethylbenzene (30‰) were observed despite the formation of side-chain oxidation products, suggesting that ring addition has a larger contribution to isotope fractionation. Dual element isotope slopes (∆δ(2)H/∆δ(13)C) therefore allow identification of significant degradation pathways of aromatic compounds by photochemically induced OH radicals. Issues that should be addressed in future studies include quantitative determination of the contribution of each competing pathway to the observed isotope fractionation and characterization of physical processes preceding the reaction that could affect isotope fractionation. PMID:26520272
Activity of 3-Ketosteroid 9α-Hydroxylase (KshAB) Indicates Cholesterol Side Chain and Ring Degradation Occur Simultaneously in Mycobacterium tuberculosis*
Capyk, Jenna K.; Casabon, Israël; Gruninger, Robert; Strynadka, Natalie C.; Eltis, Lindsay D.
Mycobacterium tuberculosis (Mtb), a significant global pathogen, contains a cholesterol catabolic pathway. Although the precise role of cholesterol catabolism in Mtb remains unclear, the Rieske monooxygenase in this pathway, 3-ketosteroid 9α-hydroxylase (KshAB), has been identified as a virulence factor. To investigate the physiological substrate of KshAB, a rhodococcal acyl-CoA synthetase was used to produce the coenzyme A thioesters of two cholesterol derivatives: 3-oxo-23,24-bisnorchol-4-en-22-oic acid (forming 4-BNC-CoA) and 3-oxo-23,24-bisnorchola-1,4-dien-22-oic acid (forming 1,4-BNC-CoA). The apparent specificity constant (kcat/Km) of KshAB for the CoA thioester substrates was 20–30 times that for the corresponding 17-keto compounds previously proposed as physiological substrates. The apparent KmO2 was 90 ± 10 μm in the presence of 1,4-BNC-CoA, consistent with the value for two other cholesterol catabolic oxygenases. The Δ1 ketosteroid dehydrogenase KstD acted with KshAB to cleave steroid ring B with a specific activity eight times greater for a CoA thioester than the corresponding ketone. Finally, modeling 1,4-BNC-CoA into the KshA crystal structure suggested that the CoA moiety binds in a pocket at the mouth of the active site channel and could contribute to substrate specificity. These results indicate that the physiological substrates of KshAB are CoA thioester intermediates of cholesterol side chain degradation and that side chain and ring degradation occur concurrently in Mtb. This finding has implications for steroid metabolites potentially released by the pathogen during infection and for the design of inhibitors for cholesterol-degrading enzymes. The methodologies and rhodococcal enzymes used to generate thioesters will facilitate the further study of cholesterol catabolism. PMID:21987574
Sortase Enzyme-Mediated Generation of Site-Specifically Conjugated Antibody Drug Conjugates with High In Vitro and In Vivo Potency
Beerli, Roger R.; Hell, Tamara; Merkel, Anna S.; Grawunder, Ulf
Antibody drug conjugates (ADCs) have recently been proven to be highly potent anti-tumor drugs, typically exceeding the efficacy of conventional monoclonal antibodies (mAbs). ADCs are currently produced by chemical conjugation of a small-molecule toxin to the mAb through lysine or cysteine side chains. This leads to heterogeneous mixtures of ADCs in which variable numbers of drugs are conjugated to individual antibodies and in which the site of conjugation cannot be defined. Consequently, there is currently significant interest in further development of drug conjugation technologies, with a particular focus on site-specific payload conjugation. Here, we present an enzymatic conjugation platform based on the S. aureus sortase A-mediated transpeptidation reaction, allowing the efficient generation of ADCs with toxins conjugated to pre-defined sites at pre-defined drug-to-antibody ratios. For this, two modifications were introduced: first, immunoglobulin heavy (IgH) and light (IgL) chains were modified at their C-termini by addition of the sortase A recognition motif LPETG, and second, the small molecule tubulin polymerization inhibitors monomethylauristatin E (MMAE) and maytansine were modified by addition of a pentaglycine peptide, thus making them suitable substrates for sortase A-mediated transpeptidation. We demonstrate efficient generation and characterization of the anti-CD30 ADC Ac10-vcPAB-MMAE, an enzymatically conjugated counterpart of brentuximab vedotin (Adcetris), as well as several anti-HER-2 ADCs including trastuzumab-maytansine, the counterpart of trastuzumab emtansine (Kadcyla). ADCs generated in this manner were found to display in vitro cell killing activities indistinguishable from the classic conjugates. Further, when tested in vivo in a HER-2-overexpressing ovarian cancer xenograft mouse model, enzymatically generated trastuzumab-maytansine was found to lead to complete regression of established tumors, similar to Kadcyla. PMID:26132162
Using Molecular Simulations to Link Chemical and Physical Features of Conjugated Polymers and Fullerene Derivatives to Bulk Heterojunction Morphology for Organic Photovoltaics
NASA Astrophysics Data System (ADS)
Marsh, Hilary; Jankowski, Eric; Jayaraman, Arthi
The morphology of blends of conjugated polymers (electron donors) and fullerene derivatives (electron acceptors) strongly affects the charge transport, charge separation and the overall efficiency of organic photovoltaic devices. In this talk we will present coarse-grained molecular simulation studies to understand how molecular-level features such as alkyl side chain length, alkyl side chain spacing along thiophene polymer backbone and fullerene functionalization (and in turn miscibility with the conjugated polymer) affect the blend morphology. Our coarse-grained models are validated by reproducing neat polymer (without acceptors) morphologies observed in experiments, such as lamellae and hexagonally packed cylinders. Furthermore, for blends of conjugated polymers and fullerene derivatives, this work shows how conjugated polymer architecture and acceptor miscibility can be tuned to obtain new blend morphologies with features that are known to enhance efficiency of organic solar cells.
Effects of surface-active block copolymers with oxyethylene and fluoroalkyl side chains on the antifouling performance of silicone-based films.
Martinelli, Elisa; Gunes, Deniz; Wenning, Brandon M; Ober, Christopher K; Finlay, John A; Callow, Maureen E; Callow, James A; Di Fino, Alessio; Clare, Anthony S; Galli, Giancarlo
Block copolymers made from a poly(dimethyl siloxane) (Si) and a poly(meth)acrylate carrying oxyethylene (EG) or fluoroalkyl (AF) side chains were synthesized and incorporated as surface-active components into a silicone matrix to produce cross-linked films with different surface hydrophilicity/phobicity. Near-edge X-ray absorption fine structure (NEXAFS) studies showed that film surfaces containing Si-EG were largely populated by the siloxane, with the oxyethylene chains present only to a minor extent. In contrast, the fluorinated block was selectively segregated to the polymer-air interface in films containing Si-AF as probed by NEXAFS and X-ray photoelectron spectroscopy (XPS) analyses. Such differences in surface composition were reflected in the biological performance of the coatings. While the films with Si-EG showed a higher removal of both Ulva linza sporelings and Balanus amphitrite juveniles than the silicone control, those with Si-AF exhibited excellent antifouling properties, preventing the settlement of cyprids of B. amphitrite. PMID:26769148
From polymers to proteins: the effect of side chains and broken symmetry on the formation of secondary structures within a Wang-Landau approach.
Škrbić, Tatjana; Badasyan, Artem; Hoang, Trinh Xuan; Podgornik, Rudolf; Giacometti, Achille
We use a micro-canonical Wang-Landau technique to study the equilibrium properties of a single flexible homopolymer where consecutive monomers are represented by impenetrable hard spherical beads tangential to each other, and non-consecutive monomers interact via a square-well potential. To mimic the characteristics of a protein-like system, the model is then refined in two different directions. Firstly, by allowing partial overlap between consecutive beads, we break the spherical symmetry and thus provide a severe constraint on the possible conformations of the chain. Alternatively, we introduce additional spherical beads at specific positions in the direction normal to the backbone, to represent the steric hindrance of the side chains in real proteins. Finally, we consider also a combination of these two ingredients. In all three systems, we obtain the full phase diagram in the temperature-interaction range plane and find the presence of helicoidal structures at low temperatures in the intermediate range of interactions. The effect of the range of the square-well attraction is highlighted, and shown to play a role similar to that found in simple liquids and polymers. Perspectives in terms of protein folding are finally discussed. PMID:27137225
A Computational Study of the Mechanism of Succinimide Formation in the Asn-His Sequence: Intramolecular Catalysis by the His Side Chain.
Takahashi, Ohgi; Manabe, Noriyoshi; Kirikoshi, Ryota
The rates of deamidation reactions of asparagine (Asn) residues which occur spontaneously and nonenzymatically in peptides and proteins via the succinimide intermediate are known to be strongly dependent on the nature of the following residue on the carboxyl side (Xxx). The formation of the succinimide intermediate is by far the fastest when Xxx is glycine (Gly), the smallest amino acid residue, while extremely slow when Xxx is bulky such as isoleucine (Ile) and valine (Val). In this respect, it is very interesting to note that the succinimide formation is definitely accelerated when Xxx is histidine (His) despite its large size. In this paper, we computationally show that, in an Asn-His sequence, the His side-chain imidazole group (in the neutral Nε-protonated form) can specifically catalyze the formation of the tetrahedral intermediate in the succinimide formation by mediating a proton transfer. The calculations were performed for Ace-Asn-His-Nme (Ace = acetyl, Nme = methylamino) as a model compound by the density functional theory with the B3LYP functional and the 6-31+G(d,p) basis set. We also show that the tetrahedral intermediate, once protonated at the NH₂ group, easily releases an ammonia molecule to give the succinimide species. PMID:27005609
RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects.
Kawata, Kohei; Morishita, Ken-ichi; Nakayama, Mariko; Yamada, Shoya; Kobayashi, Toshiki; Furusawa, Yuki; Arimoto-Kobayashi, Sakae; Oohashi, Toshitaka; Makishima, Makoto; Naitou, Hirotaka; Ishitsubo, Erika; Tokiwa, Hiroaki; Tai, Akihiro; Kakuta, Hiroki
We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5. PMID:25486327
Conjugated Polymers Atypically Prepared in Water
Invernale, Michael A.; Pendergraph, Samuel A.; Yavuz, Mustafa S.; Ombaba, Matthew; Sotzing, Gregory A.
Processability remains a fundamental issue for the implementation of conducting polymer technology. A simple synthetic route towards processable precursors to conducting polymers (main chain and side chain) was developed using commercially available materials. These soluble precursor systems were converted to conjugated polymers electrochemically in aqueous media, offering a cheaper and greener method of processing. Oxidative conversion in aqueous and organic media each produced equivalent electrochromics. The precursor method enhances the yield of the electrochromic polymer obtained over that of electrodeposition, and it relies on a less corruptible electrolyte bath. However, electrochemical conversion of the precursor polymers often relies on organic salts and solvents. The ability to achieve oxidative conversion in brine offers a less costly and a more environmentally friendly processing step. It is also beneficial for biological applications. The electrochromics obtained herein were evaluated for electronic, spectral, and morphological properties. PMID:20959869
Threonine side chain conformational population distribution of a type I antifreeze protein on interacting with ice surface studied via ¹³C-¹⁵N dynamic REDOR NMR.
Mao, Yougang; Jeong, Myongho; Wang, Tieli; Ba, Yong
Antifreeze proteins (AFPs) provide survival mechanism for species living in subzero environments by lowering the freezing points of their body fluids effectively. The mechanism is attributed to AFPs' ability to inhibit the growth of seed ice crystals through adsorption on specific ice surfaces. We have applied dynamic REDOR (Rotational Echo Double Resonance) solid state NMR to study the threonine (Thr) side chain conformational population distribution of a site-specific Thr ¹³C(γ) and ¹⁵N doubly labeled type I AFP in frozen aqueous solution. It is known that the Thr side chains together with those of the 4th and 8th Alanine (Ala) residues commencing from the Thrs (the 1st) in the four 11-residue repeat units form the peptide ice-binding surface. The conformational information can provide structural insight with regard to how the AFP side chains structurally interact with the ice surface. χ-squared statistical analysis of the experimental REDOR data in fitting the theoretically calculated dynamic REDOR fraction curves indicates that when the AFP interacted with the ice surface in the frozen AFP solution, the conformations of the Thr side chains changed from the anti-conformations, as in the AFP crystal structure, to partial population in the anti-conformation and partial population in the two gauche conformations. This change together with the structural analysis indicates that the simultaneous interactions of the methyl groups and the hydroxyl groups of the Thr side chains with the ice surface could be the reason for the conformational population change. The analysis of the theoretical dynamic REDOR fraction curves shows that the set of experimental REDOR data may fit a number of theoretical curves with different population distributions. Thus, other structural information is needed to assist in determining the conformational population distribution of the Thr side chains. PMID:21470833
Side chain modified 5-deazafolate and 5-deazatetrahydrofolate analogues as mammalian folylpolyglutamate synthetase and glycinamide ribonucleotide formyltransferase inhibitors: synthesis and in vitro biological evaluation.
Rosowsky, A; Forsch, R A; Reich, V E; Freisheim, J H; Moran, R G
5-Deazafolate and 5-deazatetrahydrofolate (DATHF) analogues with the glutamic acid side chain replaced by homocysteic acid (HCysA), 2-amino-4-phosphonobutanoic acid (APBA), and ornithine (Orn) were synthesized as part of a larger program directed toward inhibitors of folylpolyglutamate synthetase (FPGS) as probes of the FPGS active site and as potential therapeutic agents. The tetrahydro compounds were also of interest as non-polyglutamatable inhibitors of the purine biosynthetic enzyme glycinamide ribonucleotide formyltransferase (GARFT). Reductive coupling of N2-acetamido-6-formylpyrido[2,3-d]pyrimidin-4(3H)-one with 4-aminobenzoic acid, followed by N10-formylation, mixed anhydride condensation of the resultant N2-acetyl-N10-formyl-5- deazapteroic acid with L-homocysteic acid, and removal of the N2-acetyl and N10-formyl groups with NaOH, afforded N-(5-deazapteroyl)-L-homocysteic acid (5-dPteHCysA). Mixed anhydride condensation of N2-acetyl-N10-formyl- 5-deazapteroic acid with methyl D,L-2-amino-4-(diethoxyphosphinyl)butanoic acid, followed by consecutive treatment with Me3SiBr and NaOH, yielded D,L-2-[(5-deazapteroyl)amino]-4-phosphonobutanoic acid (5-dPteAPBA). Treatment with NaOH alone led to retention of one ethyl ester group on the phosphonate moiety. Catalytic hydrogenation of N2-acetyl-N10-formyl-5-deazapteroic acid followed by mixed anhydride condensation with methyl L-homocysteate and deprotection with NaOH afforded N-(5,6,7,8-tetrahydro-5-deazapteroyl)-L-homocysteic acid (5-dH4PteHCysA). Similar chemistry starting from methyl D,L-2-amino-4-(diethoxyphosphinyl)butanoic acid and methyl N delta-(benzyloxycarbonyl)-L-ornithinate yielded D,L-2-[(5-deaza-5,6,7,8-tetrahydropteroyl)amino]-4-phosphonobut ano ic acid (5-dH4Pte-APBA) and N alpha-(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine (5-dH4PteOrn), respectively. The 5-deazafolate analogues were inhibitors of mouse liver FPGS, and the DATHF analogues inhibited both mouse FPGS and mouse leukemic cell GARFT
Vibrational analysis of amino acids and short peptides in hydrated media. VIII. Amino acids with aromatic side chains: L-phenylalanine, L-tyrosine, and L-tryptophan.
Hernández, Belén; Pflüger, Fernando; Adenier, Alain; Kruglik, Sergei G; Ghomi, Mahmoud
Four out of the 20 natural α-amino acids (α-AAs) contain aromatic rings in their side chains. In a recent paper (J. Phys. Chem. B 2010, 114, 9072-9083), we have analyzed the structural and vibrational features of l-histidine, one of the potent elements of this series. Here, we report on the three remaining members of this family, i.e., l-phenylalanine, l-tyrosine, and l-tryptophan. Their solution (H(2)O and D(2)O) Raman scattering and Fourier transform infrared absorption attenuated total reflection (FT-IR ATR) spectra were measured at room temperature from the species corresponding to those existing at physiological conditions. Because of the very low water solubility of tyrosine, special attention was paid to avoid any artifact concerning the report of the vibrational spectra corresponding to nondissolved powder of this AA in aqueous solution. Finally, we could obtain for the first time the Raman and FT-IR spectra of tyrosine at very low concentration (2.3 mM) upon long accumulation time. To clarify this point, those vibrational spectra of tyrosine recorded either in the solid phase or in a heterogeneous state, where dissolved and nondissolved species of this AA coexist in aqueous solution, are also provided as Supporting Information . To carry out a discussion on the general geometrical and vibrational behavior of these AAs, we resorted to quantum mechanical calculations at the DFT/B3LYP/6-31++G* level, allowing (i) determination of potential energy surfaces of these AAs in a continuum solvent as a function of the torsion angles χ(1) and χ(2), defining the conformation of each aromatic side chain around C(α)-C(β) and C(β)-C(γ) bonds, respectively; (ii) analysis of geometrical features of the AAs surrounded by clusters of n explicit (n = 5-7) water molecules interacting with the backbone and aromatic rings; and (iii) assignment of the observed vibrational modes by means of the theoretical data provided by the lowest energy conformers of explicitly
Roles of aromatic side chains and template effects of the hydrophobic cavity of a self-assembled peptide nanoarchitecture for anisotropic growth of gold nanocrystals.
Tomizaki, Kin-ya; Kishioka, Kohei; Kobayashi, Hiroki; Kobayashi, Akitsugu; Yamada, Naoki; Kataoka, Shunsuke; Imai, Takahito; Kasuno, Megumi
Gold nanocrystals are promising as catalysts and for use in sensing/imaging systems, photonic/plasmonic devices, electronics, drug delivery systems, and for photothermal therapy due to their unique physical, chemical, and biocompatible properties. The use of various organic templates allows control of the size, shape, structure, surface modification and topology of gold nanocrystals; in particular, currently the synthesis of gold nanorods requires a cytotoxic surfactant to control morphology. To control the shape of gold nanocrystals, we previously demonstrated the de novo design and synthesis of a β-sheet-forming nonapeptide (RU006: Ac-AIAKAXKIA-NH2, X=L-2-naphthylalanine, Nal) and the fabrication of gold nanocrystals by mixing RU006 and HAuCl4 in water. The reaction afforded ultrathin gold nanoribbons 50-100 nm wide, several nanometers high, and microns long. To understand the mechanism underlying gold nanoribbon formation by the RU006 system, we here report (i) the effects of replacement of the Nal aromatic side chain in the RU006 sequence with other aromatic moieties, (ii) the electrochemical properties of aromatic side chains in the de novo designed template peptides to estimate the redox potential and number of electrons participating in the gold crystallization process, and (iii) the stoichiometry of the RU006 system for gold nanoribbon synthesis. Interestingly, RU006 bearing a naphthalene moiety (oxidation peak potential of 1.50 V vs Ag/Ag(+)) and an analog [Ant(6)]-RU006 bearing a bulky anthracene moiety (oxidation peak potential of 1.05 V vs Ag/Ag(+)) allowed the growth of anisotropic (ribbon-like) and isotropic (round) gold nanocrystals, respectively. This trend in morphology of gold nanocrystals was attributed to spatially-arranged hydrophobic cavities sufficiently large to accommodate the gold precursor and to allow directed crystal growth driven by cross-linking reactions among the naphthalene rings. Support for this mechanism was obtained by
Effect of cAMP on the cholesterol side-chain cleavage enzyme complex (CSCC) in MA-10 Leydig tumor cell mitochondria
Chaudhary, L.R.; Stocco, D.M.
The rate limiting step in steroid biosynthesis is catalyzed by the cholesterol side-chain cleavage complex (CSCC) which is located on the matrix side of the inner mitochondrial membrane. It has been shown that addition of cAMP or LH/hCG to MA-10 mouse Leydig tumor cells in culture increases the production of progesterone as the major steroid. To examine the effect of cAMP on CSCC activity, cells were grown in culture flasks in the presence or absence of 10/sup -3/M cAMP for 3 h. Cells were harvested and mitochondria were isolated. Reaction conditions were optimized and contained 465000 DPM (26-/sup 14/C)cholesterol, 10mM NaCN, 0.5mM NADPH, 5mM CaCl/sub 2/, 60mM KCl and mitochondria. Reactions were stopped by the addition of ethanol and water and liberated (26-/sup 14/C)isocaproic acid was separated from uncleaved cholesterol by extraction with hexane and chloroform resulting in the retention of isocaproic acid in the aqueous layer. These experiments demonstrated a significant increase in (/sup 14/C)isocaproic acid production by mitochondria isolated from the cells grown in the presence of cAMP when compared to controls indicating that cAMP enhances the production of progesterone by increasing the activity of CSCC. Whether cAMP brings about this increase primarily through phosphorylation/dephosphorylation reactions or through some other mechanism is not clear at this time.
A general approach to site-specific antibody drug conjugates
Tian, Feng; Lu, Yingchun; Manibusan, Anthony; Sellers, Aaron; Tran, Hon; Sun, Ying; Phuong, Trung; Barnett, Richard; Hehli, Brad; Song, Frank; DeGuzman, Michael J.; Ensari, Semsi; Pinkstaff, Jason K.; Sullivan, Lorraine M.; Biroc, Sandra L.; Cho, Ho; Schultz, Peter G.; DiJoseph, John; Dougher, Maureen; Ma, Dangshe; Dushin, Russell; Leal, Mauricio; Tchistiakova, Lioudmila; Feyfant, Eric; Gerber, Hans-Peter; Sapra, Puja
Using an expanded genetic code, antibodies with site-specifically incorporated nonnative amino acids were produced in stable cell lines derived from a CHO cell line with titers over 1 g/L. Using anti-5T4 and anti-Her2 antibodies as model systems, site-specific antibody drug conjugates (NDCs) were produced, via oxime bond formation between ketones on the side chain of the incorporated nonnative amino acid and hydroxylamine functionalized monomethyl auristatin D with either protease-cleavable or noncleavable linkers. When noncleavable linkers were used, these conjugates were highly stable and displayed improved in vitro efficacy as well as in vivo efficacy and pharmacokinetic stability in rodent models relative to conventional antibody drug conjugates conjugated through either engineered surface-exposed or reduced interchain disulfide bond cysteine resi