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A Simple Model System for the Study of
Carbohydrate-Aromatic Interactions
Giancarlo Terraneo,†Donatella Potenza,†Angeles Canales,‡
Jesus Jime ´nez-Barbero,*,‡Kim K. Baldridge,*,§and Anna Bernardi*,†
Contribution from the UniVersita' di Milano, Dipartimento di Chimica Organica e Industriale e
Centro di Eccellenza CISI, Via Venezian 21, 20133 Milano, Italy, Centro de InVestigaciones
Biolo ´gicas, Consejo Superior de InVestigaciones Cientı ´ficas, Ramiro de Maeztu 9,
28040 Madrid, Spain, and Institute of Organic Chemistry, UniVersity of Zu ¨rich,
Winterthurerstrasse 190, CH-8057 Zu ¨rich, Switzerland
Received September 14, 2006; E-mail: email@example.com; firstname.lastname@example.com; email@example.com
Abstract: A molecular scaffold was identified which enables the establishment of intramolecular interactions
between a monosaccharide and a nearby phenyl ring. A group of molecules containing four different
monosaccharides (glucose, galactose, N-acetyl-glucosamine, and N-acetyl-galactosamine) was synthesized
and used to investigate the extent and nature of this carbohydrate-arene interaction, as well as the effect
on the overall 3D structure of the molecules involved. The sugar-aromatic distance was evaluated by
rigorous NMR studies supported by molecular modeling and found to be constant throughout the series,
independent of the nature of the sugar and of the conformational behavior of the fragment connecting the
two elements. Ab initio calculations at the B3LYP/DZV(2d,p) level of theory enable the analysis of the
electronic nature of the interaction. The study shows that, given the opportunity, persistent intramolecular
aromatic-sugar interactions can be established and can significantly influence overall molecular shape
and energetics. These results have important implications in the design of structural mimics of oligosac-
Sugar-protein interactions play an important role in a wide
range of biological processes, from regulatory processes such
as fertilization to pathologies such as tumor spread. These
interactions can be responsible for mediating diverse cellular
activities, such as cell recognition, growth, and apoptosis.1,2A
large variety of proteins, with very different functions and
topologies, are involved in carbohydrate recognition, including
enzymes, periplasmic receptors, antibodies, and lectins.3Because
of the amphiphilic character of oligosaccharides, a variety of
forces mediate the recognition process, with many types of
interactions revealed in the available X-ray structures of sugar-
protein complexes. Polar groups of the sugars are bound by
H-bond donors and acceptors in the protein backbone and polar
side chains. Apolar regions (formed primarily by the pyranose
CH groups) are complemented by nonpolar surfaces of the
proteins and, in particular, tend to pack against aromatic residues
in the receptor side chains.4Convincing arguments have been
proposed that suggest that desolvation of such apolar patches
is the driving force for intermolecular interactions.5NMR studies
have shown the presence of interactions between hydrogens
belonging to the apolar faces of sugar rings and aromatic
residues of protein side chains6and have linked the strength of
the interaction to the size and the electron richness of the arene.7
In addition, studies concerning the role of N-linked oligosac-
charides during protein folding have revealed8that the incidence
of aromatic amino acids in proximity to glycans during the
folding process is higher than the standard levels occurring on
the surface or within the protein core. Together, these data
provide significant implications for molecular recognition of
carbohydrates in water solution, and indeed, artificial carbohy-
drate receptors that exploit sugar/aromatic interactions have been
described.9Carbohydrate-aromatic complexes have also been
investigated using computational methods, suggesting the
†Universita' di Milano.
‡Consejo Superior de Investigaciones Cientı ´ficas.
§University of Zu ¨rich.
(1) Lis, H.; Sharon, N. Chem. ReV. 1998, 98, 637-674.
(2) Simanek, E. E.; McGarvey, G. J.; Jablonowski, J. A.; Wong, C. H. Chem.
ReV. 1998, 98, 833-862.
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S.; Shaanan, B. J. Mol. Biol. 1998, 277, 917-932.
(5) Lemieux, R. U. Acc. Chem. Res. 1996, 29, 373-380.
(6) (a) Jime ´nez-Barbero, J.; Peters, T. NMR Spectroscopy of Glycoconjugates;
Wiley-VCH: Weinheim, Germany, 2003. (b) Wormald, M. R.; Petrescu,
A. J.; Pao, Y. L.; Glithero, A.; Elliott, T.; Dwek, R. A. Chem. ReV. 2002,
102, 371-386. (c) Jime ´nez-Barbero, J.; Asensio, J. L.; Can ˜ada, F. J.;
Poveda, A. Curr. Opin. Struct. Biol. 1999, 9, 549-555.
(7) Chavez, M. I.; Andreu, C.; Vidal, P.; Aboitiz, N.; Freire, F.; Groves, P.;
Asensio, J. L.; Asensio, G.; Muraki, M.; Can ˜ada, F. J.; Jime ´nez-Barbero,
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(8) Petrescu, A. J.; Milac, A. L.; Petrescu, S. M.; Dwek, R. A.; Wormald,
M. R. Glycobiology 2004, 14, 103-114.
(9) (a) Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. 1999, 38, 2978-
2996 and references therein. (b) Mazik, M.; Cavga, H.; Jones, P. G. J. Am.
Chem. Soc. 2005, 127, 9045-9052. (c) Klein, E.; Crump, M. P.; Davis,
A. P. Angew. Chem., Int. Ed. 2005, 44, 298-302. (d) Vacca, A.; Nativi,
C.; Cacciarini, M.; Pergoli, R.; Roelens, S. J. Am. Chem. Soc. 2004, 126,
Published on Web 02/20/2007
10.1021/ja066633g CCC: $37.00 © 2007 American Chemical Society
Page 2
interaction to be primarily intermolecular van der Waals contacts
and/or CH-π interaction.10,11,12
Carbohydrate-arene interactions have also been shown to
direct conformational equilibrium of glycophanes13and oli-
gosaccharide mimics14in water solution. We have recently
suggested that aromatic/sugar interactions may find application
in the design of glycomimetics, since intramolecular sugar/
aromatic interactions can help to stabilize bioactive conforma-
tions of small-molecule oligosaccharide mimics. In fact in the
course of our studies directed toward the synthesis of glyco-
mimetic ligands of the cholera toxin (CT),14we found clear
NMR evidence of a close spatial proximity between the phenyl
ring and the N-acetylgalactosamine residue in compound 1a
(Figure 1), which binds to CT with micromolar affinity.
Comparison with a series of analogues bearing different alkyl
groups on the ether side chain suggested that such an interaction
biases the conformational behavior of 1a by restricting the
conformational freedom of the chain. As a result, the side chain
of 1a is "preorganized" in a suitable spatial orientation that
enables optimal interaction of the binding determinants to the
binding region of CT (Figure 1).14
Sugar-aromatic interactions may have a broader application
as a key element in conformational-based design of sugar
mimics and therefore warrant further investigation. To this end,
compound 2 (Figure 2) was chosen as a suitable model to
investigate intramolecular interactions between various monosac-
charide fragments (2c-f, R ) monosaccharide) and the phenyl
ring appended to the ether side chain.
A series of molecules 2a-f with different substituents at the
axial hydroxy group of the dicarboxy cyclohexanediol15(R )
H, MOM, Glc?1-, Gal?1-, GlcNAc?1-, GalNAc?1-), were
synthesized. Compounds 2a-f can be exploited as models for
deducing chemical features and structural requirements of the
C-H vector responsible for optimal interaction with the
aromatic rings. An NMR-based approach was used to study
these features. The chemical nature of the compounds enabled
the sugar/aromatic interaction to be studied in D2O by analyzing
the nuclear Overhauser effect (NOE) observed between diag-
nostic protons belonging to the two fragments. Moreover, the
mobility of the ether chain could be studied within the series
by NOE-based methods. Spectral variations taking place in the
different glycan fragments were analyzed.
Results and Discussion.
Synthesis. The synthesis of compounds 2 followed procedures
that have been previously described for the synthesis of 1a.14
Starting from diol 3,15the monoether 5 was obtained by
regioselective alkylation with the triflate 414(45% yield; Scheme
1). The alcohol 2a was obtained from 5a by deprotection of
the benzyl ester (H2/Pd). The MOM derivative 2b was obtained
by protection of 5a (MOMCl/TBAI/DIPEA in CH2Cl2), fol-
lowed by removal of the benzyl ester (Scheme 1). Compounds
2c-f were synthesized following a common glycosylation
procedure using the sugar trichloroacetamidate as the donor and
the monoether 5b as the acceptor. The glycosylation reaction
was carried out at -30 °C and catalyzed by trimethylsilyl triflate
for glucose and galactose (2c and 2d). For the two 2-acetamido
sugars (GlcNAc and GalNAc in 2e and 2f, respectively), the
glycosylation reaction was catalyzed by triflic acid and stirred
at room temperature for 3 h before refluxing overnight in
CH2Cl2. For the entire series, the benzyl ester was removed
using H2/Pd and the acetyl groups were removed under standard
Zemplen's condition (MeONa/MeOH). Experimental details are
given as Supporting Information.
NMR Studies of Compounds 2a-f in D2O. NMR spectra
of compounds 2a-f were recorded in D2O at 400 MHz and
298-300 K. Chemical shifts and coupling constants are reported
in the Supporting Information. NOESY experiments were
carried out using a delay of 800 ms that was selected by applying
(10) Fernandez-Alonso, M.; Can ˜ada, F. J.; Jime ´nez-Barbero, J.; Cuevas, G.
J. Am. Chem. Soc. 2005, 127, 7379-7386.
(11) (a) Sujatha, M. S.; Sasidhar, Y. U.; Balaji, P. V. Biochemistry 2005, 44,
8554-8562. (b) Sujatha, M. S.; Sasidhar, Y. U.; Balaji, P. V. Protein Sci.
2004, 13, 2502-2514.
(12) Spiwok, V.; Lipovova, P.; Skalova, T.; Vondrackova, E.; Dohnalek, J.;
Hasek, J.; Kralova, B. J. Comput.-Aided Mol. Des. 2005, 19, 887-901.
(13) Morales, J. C.; Penade ´s, S. Angew. Chem., Int. Ed. 1998, 37, 654-657.
(14) Bernardi, A.; Arosio, A.; Potenza, D.; Sanchez-Medina, I.; Mari, S.; Can ˜ada,
F. J.; Jime ´nez-Barbero, J. Chem.sEur. J. 2004, 10, 4395-4406.
(15) Bernardi, A.; Arosio, D.; Manzoni, L.; Micheli, F.; Pasquarello, S.; Seneci,
P. J. Org. Chem. 2001, 66, 6209-6216.
Figure 1. Aromatic-sugar interactions stabilize the bioactive conformation
of glycomimetic 1a (see ref 14). (a) Structure of 1. (b) Preferred
conformation of 1a in water. The arrows show schematic representations
of the closed contact between aromatic and sugar residues as inferred from
NOE measurements, which were observed in the NMR spectrum of 1a in
Figure 2. Compounds used in this study and relative numbering convention.
Study of Carbohydrate−Aromatic Interactions
Page 3
the inversion recovery experiments (t1ir, Bruker library) from
50 ms to 3 s. The 800 ms delay was found to be the most
appropriate mixing time to evaluate aromatic/sugar interaction
in molecules 2c-f. NOE contact tables are collected in the
Supporting Information (Tables SI-1 to SI-6). All compounds
gave satisfactory NOESY spectra.
The relation between NOE signals and proton-proton
distances is well established16and can be worked out in a
semiquantitative manner using an interproton relaxation matrix.
The NOE intensities reflect the conformer population, and
therefore information concerning the population distribution in
solution can be obtained by focusing on the diagnostic, mutually
exclusive, NOE interactions that characterize the different
possible conformations.17A comparative analysis of compounds
2c-f reveals a series of common features throughout the series.
For all compounds, analysis of vicinal proton-proton coupling
constants for the sugar fragment indicates that all the pyranoses
are in the usual4C1conformation. The cyclohexanediol moiety
(CHD) also adopts a chair conformation, with the ester groups
in equatorial position as shown by the exclusive NOE contact
between the H2 and H4 protons on the CHD ring (Figure 2).
The orientation around the sugar-diol linkage corresponds to
the syn:syn global minimum conformation for all the monosac-
charides examined, as defined by the G1/H5CHD NOE contact
observed between the anomeric protons of the sugars and the
proton in position 5 of the diol (Figure 2).18Presence of the
alternative anti conformation would give rise to exclusive G1/
H6axCHD NOE contact, which is never observed in any of the
molecules 2c-f.
Additional degrees of freedom available to compounds 2a-f
correspond to the hydroxy acid side-chain bonds and to the
relative orientation between the monosaccharides and the
aromatic ring in compounds 2c-f. Due to the absence of
anomeric effects, the ether linkage that connects the CHD ring
to the hydroxy acid moiety is more flexible than the glycosidic
linkage. The NOE contacts observed in this region can arise
from multiple ?,ψ combinations that provide similar through-
space proton-proton interactions for the reporter HL (Figure
2). Thus, the experimental interproton distances obtained by
NMR spectroscopy can be analyzed more conveniently using
the improper dihedral angle descriptor, ?(C(O)-CR-CHDC4-
CHDH4), defined using the Newman-type projections shown
in Figure 3. This descriptor defines the orientation of HL (and
of the hydroxy acid carboxy group) relative to the CHD ring.
In principle, although rotations around the O-C bond may
also produce quasi-eclipsed orientations, three idealized stag-
gered orientations are possible involving the ether connector,
identified in Figure 3 as Conf. A (? ) 180°), Conf. B (? )
+60°), and Conf. C (? ) -60°), each associated with specific
(16) Hwang, T. L.; Shaka, A. J. J. Am. Chem. Soc. 1992, 114, 3157-3158.
(17) Dabrowski, J.; Kozar, T.; Grosskurth, H.; Nifant'ev, N. E. J. Am. Chem.
Soc. 1995, 117, 5534-5539.
(18) (a) Bernardi, A.; Potenza, D.; Capelli, A. M.; Garcı `a-Herrero, A.; Can ˜ada,
F. J.; Jime ´nez-Barbero, J. Chem.sEur. J. 2002, 8, 4597-4612. (b) Bernardi,
A.; Arosio, D.; Manzoni, L.; Monti, D.; Posteri, H.; Potenza, D.; Mari, S.;
Jime ´nez-Barbero, J. Org. Biomol. Chem. 2003, 1, 785-792.
Figure 3. Idealized staggered conformations describing the orientation of HL relative to the diol moiety (CHD). The improper dihedral angle ? (C(O)-
CR-C4CHD-H4CHD) is used to define the conformations.
Scheme 1. Synthesis of 2a-fa
a(i) Bu2SnO reflux, then 4 at rt, 5a: 33%, 5b: 45%; (ii) H2/Pd, 1 atm, rt, 2a: 95%; (iii) 1. MOMCl/TBAI/DIPEA in CH2Cl2at rt, 2. (ii) 2b: 60% over
two steps; (iv) 1. DCM/cat; 2. (ii); 3. MeONa in MeOH at rt, 2c: 61%, 2d: 69%, 2e: 64%, 2f: 70% over three steps.
Terraneo et al.
Page 4
interactions between HL and the protons on the C4, C3, and
C5 carbon atoms of the CHD ring. The primary orientations of
the hydroxy acid relative to the ring can thus be defined by
focusing on the NOE cross-peaks of the HL proton to H4, H5,
H3eq, and H3ax of the cyclohexanediol: conformer B is
associated with the exclusive HL/H5 NOE contact; conformer
A, with the HL/H3eq contact; and conformer C, with the HL/
H3ax cross-peak (Figure 3). Finally, the orientation of the
aromatic ring relative to the pyranose moiety in 2c-f can be
investigated by examining the NOE contacts between the
hydrogens on the R face of the sugar and the aromatic protons.
A first examination of the NOESY spectra shows, for most
compounds, the simultaneous presence of NOE contacts between
the HL/H5 and HL/H3eq proton pairs (Figure 4 and Table 1).
This fact suggests a fair amount of conformational freedom
within the side chain, with a general prevalence of conformer
B. These observations contrast with the spectrum of 1a, which
shows no NOE contacts between HL and H5 and a strong NOE
cross-peak between HL and H3eq.14
A quantitative evaluation of the NMR results was attempted
with the assistance of molecular modeling techniques. Both
molecular mechanics (MC/EM19) and dynamics (MC/SD20)
calculations were used. The determination of the conformational
distribution involving the ether chain of each compound,
however, involves small differences in the conformational
behavior of a flexible fragment, which is quite difficult to
describe well by computational methods. Our previous experi-
ence with similar compounds18aindicated that molecular
mechanics and dynamics calculations can provide a qualitative
reproduction of the side-chain behavior but cannot quantitatively
reproduce the experimental data. In an effort to obtain the most
accurate description of the conformational distribution of this
elusive fragment, conformer populations were generated using
three different methods and subsequently evaluated by compar-
ing predicted NOE intensities with experimentally obtained
values.21Three sets of populations were obtained, as described
in detail in the Experimental Section, from molecular dynamics
ensemble averaging (MD set), Boltzmann distributions obtained
from molecular mechanics conformational searches (MM set),
and NOE-fitting procedures (Fitting set). The experimental NOE
intensity was measured as the ratio between the volume of the
cross-peak and the volume of the corresponding diagonal peak.
The expected NOE intensity was calculated for each set of
conformations with the Noeprom22software, which uses the full
interproton relaxation matrix approach.23The accuracy of the
calculations was evaluated by measuring the percentage of NOE
intensity |exptl - theor| errors. The set of conformers that
produced the most accurate Noeprom results was then taken as
the best description of the conformational behavior of the side
chain. The results obtained for all compounds across all methods
are reported in the Supporting Information. The optimal
description obtained for each molecule is reported in Table 1.
(19) Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379-
(20) Guarnieri, F.; Still, W. C. J. Comput. Chem. 1994, 15, 1302-1310.
(21) Mari, S.; Can ˜ada, J. F.; Jime ´nez-Barbero, J., Bernardi, A.; Marcou, G.;
Motto, I.; Velter, I., Nicotra, F.; La Ferla, B. Eur. J. Org. Chem. 2006,
(22) Martin-Pastor, M. http://desoft03.usc.es/mmartin/software.html
(23) Cumming, A. C.; Carver, J. P. Biochemistry 1987, 26, 6664-6676.
Figure 4. NOESY spectra of 2a-f in D2O: NOE contacts of HL.
Table 1. Diagnostic NOESY Cross-peaks for the HL Proton and
Conformational Distribution of the Side Chaina
calculated NOE intensityb(%)
(experimental NOE intensity)c
proton pairs
2a 2b2c2d 2e 2f
A/B/C ratiod
av error %f
aSpectra recorded in D2O at 400 MHz and 300 K.bCalculated using
Noeprom.cThe NOE % is expressed as the ratio between the cross-peak
volume and the volume of the corresponding diagonal peak.dRelative
population of the limit conformations of Figure 3 which allowed the best
reproduction of the NOE cross-peak intensity.eSet of conformations that
produced the lowest error. MD, molecular dynamics; MM, multiminimi-
zation; fitting, populations from NOE data fitting with MM geometries.
fTotal error obtained for the three diagnostic contacts of Table 1.
Study of Carbohydrate−Aromatic Interactions
Page 5
The errors obtained, defined as the difference between the
experimental and calculated NOE cross-peak intensities, are
consistently lower than 3% for compounds 2b, 2c, 2d, and 2f
and 10% for compound 2e, for which the 2D-NOESY spectrum
is noisier than the others.
In order to further address the description of the ether chain
behavior in the sugar series (2c-2f), we also performed 1D
NOE and 1D ROE experiments in D2O. The buildup curves
for the NOE and ROE effect were measured at different mixing
times, and effective correlation times (τc) were estimated for
each of the proton couples involved (see Experimental Section).
It is known24that the ratio between the longitudinal and
transversal relaxation rates for a given proton pair and the related
NOE gives a mathematical function that is independent of the
distance and only depends on the effective correlation time (τc)
for that particular proton pair. Using this function, it is possible
to estimate the spectral density J(nω0) from which the inter-
proton distances can be rigorously derived (see Methods
section). This approach allows one to account for the existence
of distinct motions in different parts of the molecule and to
estimate the correlated distances for any given proton pair
without using an internal reference.
According to this analysis, all average effective correlation
times for the vectors that interconnect proton pairs of the ether
side chain with the CHD moiety are in the region 217 ( 32 ps,
which indicates that the analysis shown in Table 1 can be safely
used to address the conformational distribution. No major
differences exist among the four studied derivatives. Using the
average interproton distances for the MM clusters A and B and
the experimental interproton distances of Table 2, the confor-
mational distributions shown in Table 3 could be estimated.
In summary, for all compounds and experimental approaches
used, the R-hydroxyacid chain is found to be flexible, with
conformer C (? ) -60°) represented very little, if at all. The
majority of the conformations belong to the B cluster (? )
+60°), and the A/B ratio varies between 20:80 (2c and 2d) and
40:60 (2e and 2f) depending on the sugar (Figure 5). Stabiliza-
tion of the A cluster (? ) 180°) in the GlcNHAc- and GalNHAc-
substituted compounds 2e and 2f is likely related to the
establishment of an electrostatic interaction between the hex-
osamine NH group and the carboxy group on the ether side
chain, which in the A conformation is directed toward the sugar
The distance and orientation of the aromatic ring relative to
the monosaccharides can also be directly determined by
examining the NOE contacts between the two fragments. The
cross-peaks observed in D2O are shown in Figure 6, and their
relative intensities are reported in Table 4. The reported NOE
intensities are measured relative to the intensity of the cross-
peak between the geminal protons of the benzyl group, which
is assigned a 100% value. The protons of the phenyl ring appear
as a broad multiplet, and in the aromatic line for all compounds,
many NOE contacts are detected. Cross-peaks between the
aromatic ring, the side chain protons (HL), and the cyclohexane
ring protons (H5) are clearly observed for all compounds
examined. It is worth noting that the HAr/H5 cross-peak is
consistently more intense in the spectra of 2e and 2f, containing
GlcNAc and GalNAc, respectively. Various contacts are also
detected with the protons belonging to the R face of the sugars.
For all compounds 2c-f, HAr/G1, HAr/G3, and HAr/G5 cross-
peaks are present, all with the same intensity (ca. 10%) and
independent of the nature of the sugar. In addition, the NOESY
spectra of 2d and 2f, which are substituted with galactose and
galactosamine moieties, respectively, also display an NOE
contact between the aromatic protons and the R-proton on the
sugar 4 position (HAr/G4).
(24) (a) Poveda, A.; Santamaria, M.; Bernabe, M.; Rivera, A.; Corzo, J.; Jime ´nez-
Barbero, J. Carbohydr. Res. 1997, 304, 219-228. (b) Poveda, A.; Asensio,
J. L.; Martin-Pastor, M.; Jime ´nez-Barbero, J. J. Biomol. NMR 1997, 10,
29-43. (c) Poveda, A.; Asensio, J. L.; Martin-Pastor, M.; Jime ´nez-Barbero,
J. Carbohydr. Res. 1997, 300, 3-10.
Table 2. Correlation Time (τc) and Interproton Distances (r)
Obtained by 1D NOE and 1D ROE Experiments for the Pairs
HL/H5, HL/H4, and HL/H3eq
2c 2d2e2f
proton pair
r (Å)
r (Å)
r (Å)
average τc
203 182 253181
aCorrelation time in ps.bDistance in Å.
Table 3. Conformational Distribution of the Side Chain
Conformers Estimated from 1D NOE and 1D ROE Experiments
Conf. A/Conf. B
Figure 5. Low energy conformations of 2d showing the two main side-
chain conformations A (? ) 180°) and B (? ) +60°). The interaction
between the phenyl ring and the sugar is similar in both conformers.
Terraneo et al.
Page 6
The nature and the intensity of the contacts suggest that the
conformational freedom of the ether chain does not affect the
position of the aromatic ring to a measurable degree. This in
turn suggests that either the differences are too small to be
identified or the phenyl-sugar interaction is insensitive to the
conformational flexibility of the side chain, since the aromatic
ring can be accommodated below the sugar in both the A and
B conformations assumed by the R-hydroxyacid chain. This
latter hypothesis is supported by molecular mechanics calcula-
tions, which reveal a low-energy minimum featuring a stacked
conformation of the two rings in both the A and B clusters.
Structures found for 2d are shown in Figure 5 for illustration.
In both conformation A and B, the aromatic ring is at an average
distance of 4.2-4.4 Å from the sugar (distance between the
rings' centroids) consistently in all compounds. The interproton
distances have be evaluated quantitatively using the 1D experi-
ments described above (see Methods) and are reported in
Table 5.
The data in Table 5 clearly show that the G1-HAr distance
is indeed similar in all compounds of the series. The G3-HAr
and G5-HAr distances are also similar across all cases where
estimation could be made. The corresponding effective correla-
tion times are 170 ( 50 ps for all cases in which they were
estimated. These correlation times are somewhat shorter than
those measured between the side chain and the CHD moiety,
although not to a significant degree. These values provide an
indication that the different parts of these molecules are moving
in solution at different frequencies. Thus, all the structural and
dynamical data seem to point to the aromatic/sugar interaction
as a predominant feature in these model compounds in water
solution, occurring independent of the conformational motions
of the appended ether chain.
Computational Studies of Compound 2c. To further analyze
the nature of the carbohydrate-aromatic interaction, ab initio
calculations were performed. The optimized structure of the
glucose-substituted compound 2c, chosen as the model com-
pound, was determined at the B3LYP/DZV(2d,p) level of theory,
starting from the lowest energy B conformation located by
molecular mechanics and validated by NMR for 2c. The
hydrogen bond network resulting from the hydroxyl groups in
position G2, G3, and G4 was adopted in a counterclockwise
arrangement in order to preserve the "cascade" donor-acceptor
between the groups. Because the ?-glucose structure adopts an
all-equatorial hydroxyl position, the hydroxyl in G4 acts as a
donor for the acceptor G3, which in turns acts as a donor to the
hydroxyl in position G2, which then enables further hydrogen
bonding with the ether oxygen. In the glucose moiety the C5-
C6 bond, characterized by the torsion angle ω (O6-C6-C5-
O5), has three possible staggered conformations: gauche-trans
(gt), trans-gauche (tg), and gauche-gauche (gg) (Figure 7). In
the gt and gg conformations, the G6 hydroxyl acts as a donor
to the intraring oxygen; in the tg conformation, the G6 hydroxyl
acts as a donor to the G4 hydroxyl group. To better understand
the implications of this conformational freedom on the sugar-
aromatic interaction, we investigated the gt, tg, and gg conform-
ers of 2c. Their energy differences are shown in Table 6,
together with the distance between the aromatic ring and the
Figure 6. NOESY spectra of 2c-f (400 MHz): the line of the aromatic protons (HAr) in D2O.
Table 4. Intensity of the NOESY Cross-peaks between the
Aromatic Protons and Those on the Monosaccharide Ring in
Compounds 2c-f (D2O, 400 MHz)a
aNOE % relative to the intensity of the cross-peak between the geminal
protons of the benzyl group, which is assigned 100% intensity.bG1 and
H5 overlap.cNot detected.dG3, G5, and one of the benzyl proton overlaps.
eG3 and G5 overlap.
Table 5. Correlation Time (τc) and Distances (r) between
Aromatic Protons (HAr) and Sugar Protons Obtained by 1D NOE
and 1D ROE Experiments
2c2d 2e 2f
1583.13 122 3.05
aCorrelation time (τc) in ps.bDistance in Å.cNot detected because
signal overlaps.dNot estimated.
Study of Carbohydrate−Aromatic Interactions
Page 7
glucose moiety. The calculated energy differences for the three
conformers of 2c (gt, tg, gg, see Table 6) are in qualitative
agreement with the experimental rotamer distribution in the solid
state,25in solution,26and with ab initio calculations performed
on ?-methyl glucoside.27The distance between the aromatic ring
and the sugar ring does not appear to be affected by the C5-
C6 rotamer.
Single-point MP2/DZV(2d,p)//B3LYP/DZV(2d,p) calcula-
tions provide more accurate estimates of the relative energies
for such interactions and are reported in Table 6. The rotamer
distribution obtained at this level of theory (gt/tg/gg, 46:13:48
at 300 K) is close to the experimental data25,26and consistent
with similar population of the gg and gt rotamers and low
contribution of the tg conformer.
An estimate of the interaction energy (Eint) between the Glc-
fragment and the CHD-fragment in compound 2c was ap-
proximated from the calculated values as
Here, Emolis the calculated energy of compound 2c, and Emon
is the calculated energy of the Glc-fragment (EGlc) with the
CHD-fragment (ECHD). Full geometry optimizations were
performed for all components, and the proper isodesmic
relationship was established. To achieve this relationship, the
two monomers were obtained by fragmenting at the glycosylic
bond (C1Glc-O-C5CDH), followed by saturating the remaining
structures with hydrogens, as appropriate (Figure 8). For glucose,
we have kept the terminal bond as R-OH, and for the CHD-
fragment, the fragmentation is fixed as CHD-OH. The isodes-
mic relatonship is balanced with one molecule of water (Ewater).
The resulting isodesmic relationship for 2c together with the
two monomers (C21H31O10) provides the energy of interaction
The components of Eint have been fully optimized at the
B3LYP/DZV(2d,p) level of theory for each conformation of
2c. All the energies and geometrical parameters are available
in the Supporting Information.
The calculated interaction energies (Eint) for each conforma-
tional variant of 2c are shown in Table 7. The three interaction
energies are very similar, all around 5 kcal/mol, favoring the
complex Emon. These results would suggest that loss of the
glucose moiety from a position above the aromatic ring involves
(25) (a) Jeffrey, G. A.; McMullan, R. K.; Takagi, S. Acta Crystallogr., Sect. B
1977, 33, 728-737. (b) Marchessault, R. H.; Perez, S. Biopolymers 1979,
18, 2369-2374.
(26) Ohrui, H.; Nishida, Y.; Watanabe, M.; Hori, H.; Meguro, H. Tetrahedron
Lett. 1985, 26, 3251-3254.
(27) Kirschner K. K.; Woods R. J. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
Figure 7. Three staggered (ω-angle) calculated conformations of 2c.
Table 6. B3LYP/DZV(2d,p) and MP2/DZV(2d,p)//B3LYP/
DZV(2d,p) Calculated Relative Energies for the Three Staggered
Conformations (ω-Angle) of 2c
0.0 (0.0)
2.60 (0.62)
1.13 (0.21)
0.12 (0.03)
3.24 (0.77)
0.0 (0.0)
akJ/mol; values in parentheses are kcal/mol at B3LYP/DZV(2d,p).
bDistance between the glucose centroid and centroid of aromatic ring at
optimized geometry at B3YLP/DZV(2d,p).ckJ/mol; values in parentheses
are kcal/mol at MP2/DZV(2d,p)//B3LYP/DZV(2d,p) and correspond to a
46:13:48 population distribution at 300 K.
Figure 8. Molecular components exemplified as used for calculation of
interaction energies, Eint. Elements in red indicate placement of bonds that
are made and broken.
Eint) Emol- Emon
Eint) [(Emol+ Ewater) - (EGlc+ ECHD)]
Terraneo et al.
Page 8
a decrease in stabilization for the entire system. This behavior
reinforces our notion that sugar-aromatic interactions have an
electrostatic character that provides energy stabilization on the
order of roughly 5 kcal/mol, for these types of systems. Such
interaction magnitudes constitute weak interactions of the wdV
type and are consistent with previously reported values.10-12
As well, one can deduce that 5 kcal/mol roughly accounts for
the sum of the contributions between the hydrogens on the
R-face of the sugar (G1, G3, and G5) and the π-system of the
aromatic ring.
We have also evaluated this interaction energy using more
conventional MP2 methods, as they have been shown to be a
more accurate assessment of weak interactions in many exam-
ples. As such, we report MP2/DZV(2d,p)//B3LYP/DZV(2d,p)
Eintas described above and reported in Table 8. In fact, for this
particular analysis, the MP2 calculations are in agreement with
the B3LYP values, with the same trend of relative energy
interactions predicted.
The analysis of weak interactions is notoriously controver-
sial.28In particular, verification of interaction and identification
of the stabilizing atom-atom interactions between these two
fragments is quite difficult; therefore we have considered several
possibilities. For these investigations, we have concentrated on
(28) (a) Dunitz, J. D.; Gavezzotti, A. Angew. Chem., Int. Ed. 2005, 44, 1766-
1787. (b) Gatti, C. Z. Kristallogr. 2005, 220, 399-457.
Figure 9. (a) CPK surface. (b) Calculated molecular orbital, HOMO-6, displayed with isosurface ( 0.01 contours.
Figure 10. 2c-gt conformation: views a and b. Electrostatic potential mapped on electron density isosurfaces of 2c in the a and b view: c and d (isosurface
0.002 au), e and f (isosurface 0.005 au), and g and h (isosurface 0.007 au), respectively.
Table 7. Interaction Energy (Eint) for 2c (gt, tg, and gg) Using Full
Geometry Optimization at the B3LYP/DZV(2d,p) Level
Table 8. Relative Interaction Energy (Eint) for DFT and MP2
aB3LYP/DZV(2d,p) interaction energy (Eint) at B3LYP/DZV(2d,p)
optimized geometries.bB3LYP/DZV(2d,p) relative interaction energy (Eint)
at B3LYP/DZV(2d,p) optimized geometries.cMP2/DZV(2d,p) relative
interaction energy (Eint) at the B3LYP/DZV(2d,p) optimized geometries.
Study of Carbohydrate−Aromatic Interactions
Page 9
the structure with the lowest complexation energy, Eint, con-
former gt. In Figure 9a, the CPK29surface of 2c-gt is displayed,
illustrating the G3 hydrogen to be within van der Waals contact
of the aromatic ring and the G1 and G5 hydrogens to be
extremely close to the van der Waals surface of the ring.
A further representation of the sugar/aromatic interaction for
this model is provided by the analysis and visualization of the
molecular orbital structure, displayed in Figure 9b. In fact,
molecular orbital HOMO-6, where HOMO is the highest
occupied molecular orbital, shows a bonding interaction between
the sugar moiety and the aromatic ring, i.e., the G1, G3, and
G5 hydrogens and the aromatic ring. The fact that this interaction
is placed well below the HOMO (EHOMO-6 ) -4.580 eV)
suggests a strong contribution toward the stability of the system.
The intramolecular distances between the aromatic centroid
(CAr) and the sugar protons for the compound 2c are in the
range of NOE contacts (CAr-G1 ) 3.50 Å, CAr-G3 ) 3.03
Å, and CAr-G5 ) 3.87 Å).
Further assessment of the weak complex interaction can be
evaluated using electrostatic potential contour maps. The
electrostatic potential (ESP) of 2c was mapped onto the total
electron density as calculated from the ab initio methods and
various contours evaluated in succession for illustrative pur-
poses. The electron density isosurfaces evaluated begin from
isosurface 0.002 au, representing >98% of the electronic charge,
to isosurface 0.007 au, (i.e., closer to the nucleus), representing
an increase of 4.39 kcal/mol for the electronic charge. All
isosurfaces are mapped in the same range of ESP value ((0.223
au), and the contour colors represent the range including the
most electron-rich areas (red) to the most electron-poor areas
(blue). In this case, since there is a negative charge on the
carboxyl group, the entire molecule shows negative character.
Figure 10a and b show two different views of the complex
involving 2c, with indicated levels of isosurface displayed for
each in Figure 10c-h. Figure 10c and d show the isosurfaces
0.002 au and are analogous to the contour surface view offered
by the CPK method. The relative ESP surface around the G1
and G3 hydrogens clearly indicates contact with the aromatic
ring, suggesting and confirming the intermolecular bonding-
type CH-π interaction, between the aromatic ring and the sugar
moiety. Further illustration of this phenomena is observed by
displaying the other surfaces, Figure 10e and f, at isosurface
0.005 au, encompassing a slightly smaller magnitude of electron
density, and showing the G3/aromatic ring as still intact, again
suggesting strong interaction between the two moieties at this
hydrogen position. Moving yet closer to the nuclei, Figure 10g
and 10h, at isocontour 0.007 au, now show no contact between
any of the hydrogens on the R-face of the sugar with the
aromatic ring. Together, this analysis enables an estimation of
the extent of the weak interaction, placed between 0.002 au and
0.007 au or between 1.2 and 4.4 kcal/mol.
Compound 2 was chosen as a model for investigating the
nature of intramolecular interactions between four different
monosaccharides (glucose, galactose, N-acetyl-glucosamine, and
N-acetyl-galactosamine in 2c-f, respectively) and the phenyl
ring appended to the ether side chain. NMR studies supported
by molecular modeling and ab initio calculations led to several
conclusions concerning the nature of the sugar/aromatic type
interaction and the effect on the 3D structure of the molecules
As revealed by NOE measurements, the phenyl ring and the
monosaccharides appear to adopt a well-defined orientation,
which is consistent across the series examined. NOESY spectra
of 2c did not depend on the solution pH in the range 3.6-7,
and the intensity and position of the observed cross-peaks were
identical for the corresponding methyl ester,30thus ruling out a
major contribution of the carboxy group to the establishment
of the molecular conformation. The sugar-aromatic distance
was evaluated by rigorous NMR studies supported by molecular
modeling and found to be constant throughout the series and
independent of the nature of the sugar. Since all the aromatic
proton signals strongly overlap in the spectra examined, the
analysis of the NOE contacts may have missed some fine details
of the possible differences in sugar-aromatic orientation.
However, it is worth noting that the above conclusion is
supported both by the molecular modeling results and by DFT
calculations (B3LYP/DZV(2d,p)) not described here.30Thus it
appears that, given the opportunity, persistent intramolecular
aromatic sugar interactions are established in small molecules
and can significantly influence the oVerall molecular shape. This
is not to say that all the remaining internal degrees of freedom
can be frozen or fully controlled by exploiting the formation of
a sugar/aromatic intramolecular complex: indeed the work
reported here shows that the mobility of the ether side chain in
compounds 2c-f does display some variation as a function of
the carbohydrate involved. Furthermore, the dynamic behavior
of the side chain in the unglycosylated compounds 2a-b does
not differ significantly from that observed in the glycosylated
set (see Table 1), whereas our previous studies show that it is
significantly influenced by the configuration of the included
stereocenter.18aRather it seems that the soft nature and low
directionality of the sugar/aromatic interaction enables the
structure to be resiliently conserved despite other molecular
changes. This, in turn, allows the molecule to maintain its global
shape. Such behavior can have important implications in the
design of structural mimics of oligosaccharides, as we have
found serendipitously in the course of previous studies.14This
type of mechanism could also be at work in the formation of
sugar/lectin complexes and fits well the current understanding
of the sugar code as an exquisitely tunable one.31
Ab initio calculations suggest an energy in the range of 5
kcal/mol for the sugar/aromatic type interaction. This estimate
is in agreement with previously reported values.10-12Aromatic-
sugar contacts have been previously suggested as driven by CH/
π,10-12van der Waals,32or hydrophobic33interactions. More
generally, the nature and origin of weak interactions in
molecules and crystals are the subject of intense and heated
debate.28In our previous studies14we observed that 1b (Figure
1), the cyclohexyl analogue of 1a, had a dynamic behavior very
different from that of 1a and did not display any NOE contacts
between the cyclohexyl ring and the carbohydrate portion. Visual
inspection of the combined ab initio and density functional
(29) Gavezzotti, A. J. Am. Chem. Soc. 1983, 105, 5220-5225.
(30) Terraneo, G. Ph.D. thesis, Universita' di Milano, Milano, Italy, 2006.
(31) Gabius, H-J.; Siebert, H.-C.; Andre ´, S.; Jime ´nez-Barbero, J.; Ru ¨diger, H.
ChemBioChem 2004, 5, 740-764.
(32) Toone, E. J. Curr. Opin. Struct. Biol. 1994, 4, 719-728 and references
(33) Elgavish, S.; Shaanan, B. Trends Biochem. Sci. 1997, 22, 462-467.
Terraneo et al.
Page 10
model of 2c in Figure 9 shows that the apolar hydrogen atoms
on the R-face of the sugar are in proximity with the van der
Waals surface of the aromatic residue, and the molecular orbital
representation of the HOMO-6 orbital (Figure 9b) indicates a
stabilizing bonding interaction between the sugar CH vectors
and the aromatic ring. The electrostatic potential of the aromatic
ring (Figure 10) appears slightly more positive on the face which
is in contact with the sugar, suggesting that the sugar CHs are
acting as weak acids on the π-electron cloud of the phenyl ring.
Preliminary results obtained from NOESY spectra of 2c in
CD3OD solution30appear to indicate a weakening of the NOE
contacts and possibly suggest a role for hydrophobic packing
in defining the molecule conformation. In light of the above
observations, the interaction between the aromatic ring and the
carbohydrate fragment in 2c-f could be best described as a
relatively extended contact between the two hydrophobic
surfaces involving significant electron overlap.
Aromatic amino acid residues are often present in the binding
sites of carbohydrate-binding proteins. The resulting carbohy-
drate-protein complexes are characterized by a placement of
the sugar in a roughly parallel orientation relative to the plane
of the aromatic ring, similar to the one observed in compounds
2c-f. These molecules, therefore, can serve as simple and
tunable models for study of the nature of carbohydrate-aromatic
interactions and the implications in the molecular recognition
of carbohydrates.
Experimental Section
Computational Methods. A. Molecular Mechanics Calculations
and Generation of the Three Population Sets. All calculations were
performed using the MacroModel/Batchmin 8.534package (Maestro-
version 6.0) and the AMBER* force field. Kolb's parameters were used
for the hydroxyacid moiety.35Bulk water solvation was simulated by
using MacroModel's generalized Born GB/SA continuum solvent
model,36which treats the solvent as an analytical continuum starting
near the van der Waals surface of the solute, and uses a dielectric
constant (?) of 78 for the bulk water and 1 for the molecule.
An initial conformational search was carried out using 10 000 steps
of the usage-directed MC/EM procedure following previously estab-
lished protocols.37Extended nonbonded cutoff distances (a van der
Waals cutoff of 8.0 Å and an electrostatic cutoff of 20.0 Å) were used.
The output structures were clustered based on the improper dihedral
angle descriptor ?(C(O)-CR-CHDC4-CHDH4), which describes the
side-chain conformation. Three clusters were obtained, corresponding
to Conf. A, Conf. B, and Conf. C of Figure 3. Conformations with
values of the ? improper dihedral angle in the range 180° ( 60° were
clustered in the A family, those with ? in the range 60° ( 60° were
clustered in the B family, and those with ? in the range of -60° ( 60°
were clustered in the C family. In this way all the space was investigated
in all directions, without loosing information and no conformers were
outside of the defined staggered conformations (A, B, or C). The above
criteria were used also to define the A, B, and C populations of the
following sets.
The cluster leaders were used as starting structures for the dynamics
The first conformer set (MD set) was obtained by running three MC/
SD runs of 5 ns each, starting from three conformers corresponding to
the three idealized geometries of Figure 3 (Conf. A, Conf. B, Conf. C,
15 ns total simulation) and saving 5000 structures for each run, using
an electrostatic cutoff of 20 Å, a van der Waals cutoff of 8.0 Å, and a
hydrogen bond cutoff of 4 Å. The simulation was performed at 300 K,
with a dynamic time step of 1.5 fs; the Monte Carlo acceptance ratio
was less 4%, and each accepted MC step was followed by an SD step.
Structures were sampled every 1 ps and saved for later evaluation,
monitoring both energetic and geometrical parameters. As expected,
the MC/SD protocol allowed for fast interconversion of the starting
conformers, so that the populations obtained from the individual runs
appeared to be converged within 5% and the interproton distances
differed by no more than 0.1 Å.
The second set (MM set) was obtained by Multiple Minimization
of the MD set (i.e., of the total 15 000 snapshots saved during the
molecular dynamics simulations) using the same force field and cutoff
applied in the MD set. The third set of conformations (Fitting set) was
obtained by fitting the NOE data, using a procedure that we have
recently described.21Briefly, the MM set of conformations was clustered
in the three clusters A, B, and C of Figure 3 using the ?(C(O)-CR-
CHDC4-CHDH4) descriptor as detailed above. Interproton distances
and NOE intensities (%) were derived for each cluster using a full
matrix relaxation calculation extended to all the members of each
cluster. An initial value was assigned to the weight of each cluster,
and the conformer distribution was estimated by fitting the Noeprom-
based % overall NOE intensities to the experimental ones.
B. Ab initio Calculations. Full geometry optimizations, including
structural, orbital, and various electrostatic property analysis, were
carried out using the GAMESS software package.38Structural computa-
tions were performed using hybrid density functional theory (HDFT).
The HDFT method employed Becke's three-parameter functional in
combination with a nonlocal correlation provided by the Lee-Yang-
Parr expression with both local and nonlocal terms, B3LYP.39The
DZV(2d,p) basis set40was used. Full geometry optimizations were
performed and uniquely characterized by calculating and diagonalizing
the matrix of energy second derivatives (Hessian) to determine the
number of imaginary frequencies (0 ) minima; 1 ) transition state).
All energetics and Cartesian coordinates for the optimized geometries
are available in the Supporting Information.
From the fully optimized structures, single-point energy calculations
were performed using the MP2 dynamic correlation treatment for further
analysis of energetics and properties. The optimal method was
determined using several levels of theory to establish self-consistency
in terms of basis sets as well as effects of dynamic correlation.
Additionally, these methods have been previously shown to be reliable
for the types of compounds considered here.41Molecular orbital contour
plots and electrostatic potential plots, used as an aid in the discussion
of the results, were generated using the program 3D-PLTORB42and
GAMESS, respectively, and depicted using QMView43and MOLE-
NMR Methods. NMR spectra were recorded in a 5 mM D2O
solution using Bruker AVANCE 400, at 300 K. 1D, as well as 2D,
COSY, HSQC, and NOESY experiments were recorded using the
(34) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440-467.
(35) Kolb, H. C.; Ernst, B. Chem.sEur. J. 1997, 3, 1571-1578.
(36) Still, W. C.; Tempzyk, A.; Hawley, R.; Hendrickson, T. J. Am. Chem. Soc.
1990, 112, 6127-6129.
(37) (a) Brocca, P.; Bernardi, A.; Raimondi, L.; Sonnino, S. Glycoconjugate J.
2000, 17, 283-299. (b) Bernardi, A.; Raimondi, L.; Zuccotto, F. J. Med.
Chem. 1997, 40, 1855-1862.
(38) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon,
M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S.;
Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem. 1993,
14, 1347-1363 (www.msg.ameslab.gov/GAMESS/GAMESS.html).
(39) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(40) Dunning, T. H. J. Chem. Phys. 1970, 53, 2823-2833.
(41) (a) Milet, A.; Korona, T.; Moszynski, R.; Kochanski, E. J. Chem. Phys.
1999, 111, 7727-7735. (b) Perez-Jorda, J. M.; San-Fabian, E.; Perez-
Jimenez, A. J. J. Chem. Phys. 1999, 110, 1916-192. (c) Guerra, C. F.;
Bickelhaupt, F. M. J. Chem. Phys. 2003, 119, 4262-4273. (d) Zhang, Y.;
Pan, W.; Yang, W. J. Chem. Phys. 1997, 107, 7921-7925.
(42) 3D-PLTORB; San Diego, 3D version, 1997.
(43) Baldridge, K. K.; Greenberg, J. P. J. Mol. Graphics 1995, 13, 63-68.
(44) Flu ¨kiger, P.; Lu ¨thi, H. P.; Portmann, S.; Weber, J. MOLEKEL 4.0; Swiss
Center for Scientific Computing: Manno, Switzerland, 2000.
Study of Carbohydrate−Aromatic Interactions
Page 11
standard pulse sequences. NOESY experiments were carried out using
a mixing time of 800 ms. Exclusive NOE contacts for both compounds
were identified and integrated from the NOESY spectrum relative to
the diagonal peak of the corresponding rows.
Cross-peaks from NOESY experiments were integrated using the
MestReC software45obtaining the related NOE intensities (%) as the
ratio between the diagonal peak and the cross-peak. Their intensities
were compared with those estimated by Noeprom,22as described below.
The theoretical NOE intensities were generated from the computational
models using the Noeprom software22based on a full matrix relaxation
approach46and using a rigid isotropic model.47The NOE volumes
reported in Table SI-7 (Supporting Information) correspond to a 400
MHz spectrometer, using a 800 ms mixing time and a correlation time
(τc) of 200 ps. The MD predictions were obtained as averages of all
the conformations collected during the 15 ns dynamic runs The MM
predictions were obtained as Boltzmann-weighted averages of all the
conformations obtained by Multiple Minimization of the dynamics
output, within 3 kcal/mol from the global minimum. The NOE Fitting
prediction was obtained by using the Simplex algorithm.48An initial
value was assigned to the weight of a given cluster (Conf. A, Conf. B,
and Conf. C) and an estimation of the average % NOE intensities
calculated; then, the deviation between the calculated and experimental
values was iteratively minimized (up to 10 000 steps), and thus, the
best-fitting population weights were obtained.
The Noeprom results were analyzed to estimate the % NOE intensity
errors, which are collected in Table SI-7 of the Supporting Information,
together with the associated population distributions and distances (Å).
1D Experiments. 1D NOE and 1D ROE NMR spectra were recorded
in a 5 mM solution of D2O using Bruker AVANCE 500, at 300 K
using the standard selnogp and selrogp sequence from the Bruker
library. The NOE buildup was measured at different mixing times, for
1D NOE 0.2, 0.4, 0.6, 0.8, 1 s and for 1D ROE 0.2, 0.3, 0.4, 0.5, 0.6,
0.75 s. The longitudinal relaxation rate (σnoe) and the transversals
relaxation rate (σroe) for each proton pair were calculated as the slope
of the line for mixing time vs NOE intesity. The ratio between σnoe
and σroegives a mathematical function (eq 1) that allows determining
the τc for a proton pair without knowing the distance (ω0 is the
frequency of the magnet in rad/s).
After knowing the τc,σnoe, and σroefor a proton pair, the interproton
distance for this proton couple could be calculated. The density spectral
function (J(nω0)) correlates the molecular motion and the distance, and
so, by using the eqs 2-4 the distance could be deduced.
Acknowledgment. This project was supported in part by the
European Union under Contract HPRN-CT-2002-00173 (Gly-
cidic scaffolds Network). K.K.B. acknowledges the Swiss
National Science Foundation (SNF-200021-107979) for support
of this work. We thank Dr. Carlo Gatti for the many helpful
comments and discussions.
Supporting Information Available: Experimental procedures,
compound characterization,1H NMR and13C NMR of com-
pounds 2a-f, tables of NOE contacts and conformational
analysis results for compounds 2a-f, Cartesian coordinates and
absolute energies from QM calculations of compound 2c (gt,
tg, and gg). This material is available free of charge via the
Internet at http://pubs.acs.org.
(45) Cobas, J. C.; Sardina, F. J. Concept. Magn. Reson. 2003, 19, 80-96
(46) Borgias, B. A.; James, T. L. Methods Enzymol. 1989, 176, 169-183.
(47) Lipari, G.; Szabo, A. J. Am. Chem. Soc. 1982, 104, 4546-4559.
(48) Dantzig, G. B. Linear Programming and Extension; Princeton University
Press: 1998; Chapter 5: The Simplex Method.
σnoe/σroe) (5 + ω0
2- 4ω0
4)/(5 + 22ω0
2+ 8ω0
J(nω0) ) τc/1 + (nω0τc)2
σnoe) C[6J(2ω0) - J(0)]
σroe) C[2J(0) + 3J(ω0)]
Terraneo et al.


text:
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In a step that over-ruled America's Turkish NATO ally, U.S. jets dropped food, first aid and weaponry into the besieged Syrian Kurdish town of Kobane on Monday morning.
In a moving (but of course, still funny) episode of "Last Week Tonight," John Oliver sheds light on the plight of Iraqi and Afghani translators who worked for U.S. forces and contractors, a position that jeopardized the well-being of their families as well as themselves.
Kurdish forces at Kobane (Ayn al-Arab) on Saturday fought off an assault by Islamic State that sought to cut the city off from Turkey and completely surround it, according to an Al-Jazeera reporter on the scene.
It is hard not to conclude that Iran's outbreak of optimism regarding the nuclear enrichment program has to do at least in part with the rise of Islamic State in Mosul and the consequent U.S. need for an Iranian partner.
The U.S. is again at war in the Middle East, bombing freely across Iraq and Syria and searching desperately for some non-American boots to put on the ground. Here are seven worst-case scenarios in a part of the world where the worst case has regularly been the best that's on offer.
The Pentagon released a report earlier this week detailing the threats that climate change poses in the near future.
The headlines shift hourly between Ebola and Islamic State. The question is often asked, "Should we put boots on the ground?" The answer is yes—but not in the Middle East.
According to Al-Jazeera sources, Islamic State has completed the taking of Hit district in the al-Anbar Province of Iraq.
White House/Pete Souza
The notion that Iraq will "destroy" Islamic State at American behest is an illusion, and so is the notion that the coalition just formed can do it.
There are 650 members of the British parliament, so the vote Monday by 271 of them to recognize Palestine is hardly an overwhelming victory for supporters of this position. However, the symbolic impact of the vote is quite large.
In a worrisome development, radicals throughout the region are rallying to the so-called Islamic State, which is actually just a bunch of armed thugs and brigands.
Adam Zyglis, Cagle Cartoons, The Buffalo News —
Al-Khalij reports that the Syrian Human Rights Observatory says Islamic State fighters are now in one third of the Syrian Kurdish city of Kobani.
The fall of the Yemeni government to radical Zaidi tribesmen from Saadah in the north has gone relatively unremarked upon in the U.S. mass media.
I could be mad at Vice President Joe Biden, who has been here in Los Angeles for two days and tied up traffic for miles at a time. But it's hard. He's just too nice a guy, even if he talks too much—and worse, these days, tells the truth.
The U.S. is preparing to send more military supplies to the Middle East to fight Islamic State at the same time a report has revealed that many of the radical group's weapons come from America. So how can we be sure the deadly equipment we're sending won't end up in the same hands?
Islamic State fighters have advanced into the Kurdish Syrian city of Kobani with fighting in the streets as Kurds resist, according to the pan-Arab daily al-Hayat.
U.S. Air Force/Tech. Sgt. Joseph Swafford Jr.
The decision of President Barack Obama to wage air war against the Islamic State still is swimming in a sea of confusion and doubt.
According to Turkish President Recep Tayyip Erdogan, Islamic State forces were closing in on capturing the Syrian town of Kobani on Tuesday. This development was of particular concern to Erdogan, as Kobani is close to the border between Syria and his own country.
There hasn't been a regional war of this scope since the Gulf War.
AP/Amira Mortada, El Shorouk Newspaper
Women played a significant role in the 2011-2013 revolutions that shook the heart of the Arab world, as well as in the succeeding turmoil.
Steve Sack, Cagle Cartoons, The Minneapolis Star Tribune —
The pan-Arab London daily Al-Hayat [Life] reported Sunday that Islamic State is still expanding its sway in towns in Iraq's western al-Anbar Province, having just taken Kubaisah in the district of Hit on Friday into Saturday, two days after the district capital of Hit fell to them.
Ismat Sheikh, commander of the Kurdish forces at the border town of Kobane (Ain al-Arab) that is besieged by Islamic State tanks and artillery, says that he expects massacres of its inhabitants if it falls to the Sunni Arab extremists.
The Turkish parliament voted by a large margin Thursday to allow Turkish troops to make incursions into neighboring countries if necessary to defeat the so-called Islamic State of Iraq and the Levant.
Palestine will argue that Israel has systematically and over decades violated all the international laws regulating military occupations, and that it is quickly marching toward being an apartheid state.
U.S. Navy/MC1 Trevor Welsh
Reese Erlich was in northern Iraq at the start of the U.S. bombing campaign against Islamic State. He says the reality on the ground is far different from the propaganda coming out of Washington.
As the United Kingdom joins the U.S. and others in another conflict in the Middle East, the "Trews" host analyzes what war is good for.
The GOP Congress' assault on the American working class has been waged with the pretext that the federal government has no money (what with being in debt and all).
Oh right, because Congress pretty much does diddly squat these days. Watch Jon Stewart make a jaw-dropping discovery as to why our elected officials refuse to publicly discuss what the "Daily Show" host calls one of the most "crucial issues of our time."
Israeli Prime Minister Benjamin Netanyahu delivered a speech at the U.N. to a half-empty hall in which he tried to exemplify the most logical fallacies in a short period of time.
President Obama admitted on CBS' "60 Minutes" on Sunday that the U.S. had underestimated the military potential of Islamic State.
LEE SNIDER PHOTO IMAGES / Shutterstock.com
It is something of a cliche to quote George Santayana one more time, saying, "Those who do not remember the past are condemned to repeat it." But for folks of my age, ignorant repetition has been a constant in our lives. And, of course, it is happening again right now.
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Hog Futures Slump Amid Falling U.S. Pork Demand; Cattle Steady
Nov. 14 (Bloomberg) -- Hog futures declined for the third straight day on signs that U.S. pork demand is slowing, while lower feed costs are encouraging producers to boost animal weights. Cattle prices traded little changed.
Wholesale pork fell 3.2 percent to 92.19 cents a pound yesterday, and are down 17 percent from this year's high on June 26, U.S. Department of Agriculture date show. Average hog-carcass weights climbed 2.3 percent through yesterday in the past 12 months, according to the USDA. The price of corn, the main ingredient in livestock feed, has slumped 39 percent this year on the outlook for a record crop.
"Input costs are reasonable, like corn, and we have added record weights to the hogs," Don Roose, the president of U.S. Commodities Inc. in West Des Moines, Iowa, said in a telephone interview. "It's profitable for the producer to add extra weight."
Hog futures for February settlement fell 1.1 percent to close at 89.8 cents a pound at 1 p.m. on the Chicago Mercantile Exchange. The contract dropped 1.6 percent in the previous two days.
Cattle futures for February delivery gained less than 0.1 percent to $1.34525 a pound on the CME. The most-active contract has risen 1.7 percent this year.
Feeder-cattle futures for January settlement added 0.3 percent to $1.652 a pound.
To contact the reporter on this story: Dalton Barker in Chicago at firstname.lastname@example.com
To contact the editor responsible for this story: Millie Munshi at email@example.com


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Archive for the 'Network TV Press Releases' Category
November 3rd, 2011 at 10:52 am
ABC Sweeps Daytime Across All Target Women, Ranking No. 1 in Women 18-34, 18-49 and 25-54
"The Chew" Posts 3rd Consecutive Week of Increases; Hits Series Highs in Total Viewers, Women 18-34, Women 18-49 and Women 25-54[Read-More]
November 3rd, 2011 at 10:48 am
ABC Produces its Top-Rated November Sweep Opening Wednesday in 4 Years
Posting a Best-Since Debut Adult 18-49 Rating, ABC's "Revenge" Wins Wednesday's 10pm Hour by its Biggest-Ever Margins Over Both CBS' "CSI" and[Read-More]
November 3rd, 2011 at 10:41 am
ABC Family Sets Premiere Dates for January 2012 Line Up Including 'Pretty Little Liars,' 'Switched at Birth' and 'Jane By Design'
'Pretty Little Liars' returns Monday, January 2.[Read-More]
November 3rd, 2011 at 10:18 am
CBS Stars to Take Over the Network's Facebook Pages and Twitter Feeds Nov. 5-11
Stars to Program These Social Media Sites With Commentary, Pictures, Videos, Exclusive Content and Answers to Fans Questions[Read-More]
November 3rd, 2011 at 10:06 am
Showtime Renews 'The Real L Word' with New City & Cast Members
Nine episodes season three will film in Los Angeles and New York[Read-More]
November 3rd, 2011 at 9:58 am
All New Episodes of 'Toddlers & Tiaras' & 'What Not To Wear' Return to TLC
'Toddlers & Tiaras' returns on December 7; 'What Not To Wear' on November 29.[Read-More]
November 3rd, 2011 at 9:50 am
'Survivor' Hits Another Season High In Viewers And Matches Season Best Adult 18-49 Rating
"Criminal Minds" and "CSI" Win Their Time Periods in Viewers[Read-More]
November 3rd, 2011 at 9:41 am
Drew Barrymore Joins TCM Showcase 'The Essentials' with Robert Osborne
Drew Barrymore will co-host the 12th season of Turner Classic Movies' (TCM) signature showcase: 'The Essentials.'[Read-More]


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Post Content
posted by: Katie Gorodetsky – WIC's Immunization Coordinator
Did you know that autism affects 1 in 88 children, particularly 1 in 54 boys? Autism spectrum disorders (ASDs) are a group of developmental disabilities that can cause significant social, communication, and behavioral challenges. ASDs are "spectrum disorders", meaning they affect each person in different ways and can range from very mild to severe. ASDs begin before the age of 3 and last throughout a person's life, although symptoms may improve over time. Some children with an ASD show hints of future problems within the first few months of life. In others, symptoms might not show up until 24 months or later.
One of the most important things you can do as a parent or caregiver is to learn the early signs of autism and become familiar with the typical developmental milestones that your child should be reaching.
If your child exhibits any of the following, please don't delay in asking your pediatrician or family doctor for an evaluation:
- No big smiles or other warm, joyful expressions by 6 months or thereafter
- No back-and-forth sharing of sounds, smiles or other facial expressions by 9 months
- No back-and-forth gestures such as pointing, showing, reaching or waving by 12 months
- No babbling by 12 months
- No words by 16 months
- No meaningful, two-word phrases (not including imitating or repeating) by 24 months
- Any loss of speech, babbling or social skills at any age
For a comprehensive list of behavioral milestones at specific ages, please visit http://www.cdc.gov/ncbddd/actearly/milestones/index.html.
Feeding disorders are often seen in infants and children with ASD. The most commonly reported feeding disorder is constipation. Nutritionists and occupational therapists can help to make sure that someone with ASD gets the best nutrition possible, so don't hesitate to speak to your child's doctor about getting additional services or asking for a referral to a nutritionist or Early Intervention Program. Early Intervention programs help children not only with nutrition but also with developmental skills they need to grow up healthy and happy.
If you have concerns about your child's development, please visit http://www.cdc.gov/ncbddd/actearly/concerned.html or talk to your child's doctor. Acting early can make a real difference.
For more information about autism spectrum disorders, please visit http://www.autismspeaks.org/.
Recent Posts
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At WIC, we are very fortunate to have so many staff members from different countries and cultures. In this week's blog, Kinnari Chitalia, RD, LDN, CLC, Nutritionist at the Dorchester North WIC Program, shares a favorite recipe that can be made at any time, but …Continue Reading A Taste of India for Special Occasions!
Working to Eliminate Health Disparities Among LGBT People posted on Mar 27
This week marks the commemoration of National LGBT Health Awareness Week. At DPH this is not only an occasion to celebrate the strides that we as a Commonwealth have made in reducing disparities in health care and health outcomes among people who identify as lesbian, …Continue Reading Working to Eliminate Health Disparities Among LGBT People
Weekly Flu Report, March 27, 2015 posted on Mar 27
The latest weekly flu report shows a slight decrease in rates of flu-like illness in the Commonwealth over the past seven days, which is consistent with what we would expect to see at this point of flu season. Flu does however continue to be present …Continue Reading Weekly Flu Report, March 27, 2015


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Within City
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Charles J. Carter, DDS is a General Dentistry specialist in Athens, AL.
855 Sunset Drive, Athens, GA 30606
"Dr. Robert Pate - the best dentist in Athens, GA! He provides the best dental services ever and has the best dental clinic! :-) his staffs are kind ..."
"Very nice people. Professional and helpful with questions. Good sports as well since I have a messed up sense of humor. Very informative as to what is going ..."


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Feature ArticleVisualizing Large Environmental Data Sets in a Global 4D Viewer
Makai Voyager 4D Visualization Software Aids Analysis Of Complex Hydrodynamic Plume Models for OTEC Development
By Duke J. Hartman
Marketing Manager
Greg Rocheleau
Ocean and Chemical Engineer
Dr. John C. Anderson
Technical Lead, Advanced Visualization Division
Makai Ocean Engineering Inc.
Kailua, Hawaii
Having an accurate understanding of physical environmental conditions is essential to all ocean-related industries. Numerical models, informed by sensor data, have been developed for many of these industries to describe and predict the behavior of physical systems. Recently, there has been an exponential increase in the size, quality and complexity of environmental data from surveys, sensors and numerical models.
Models often produce gigabytes or terabytes of data containing multiple variables of interest that can change in both space and time. However, the tools to process and visualize these large environmental data sets have not kept pace with the increase in data generation. Scientists, engineers and executives are facing the fundamental problem of how to efficiently manage and interpret the vast amount of oceanographic, geologic and atmospheric data being collected and modeled. Scientific and oceanographic activities are often limited to using subsets of environmental and sensor data, which increases the possibility of missing critical information. Furthermore, most data are still being presented as sequences of flat 2D images, which is an inefficient and time-consuming method of analyzing data that is inherently 3D and 4D (3D plus time).
Well-known, highly interactive software systems that are used to view large amounts of terrain and image data, such as Google Earth, Microsoft Virtual Earth and the leading GIS software, are not capable of displaying large scientific data sets, such as volumetric (3D) data that changes in time (4D). They are primarily restricted to displaying imagery, terrain and static 3D objects. On the other hand, many existing scientific programs were not designed to easily incorporate georeferenced data such as lidar point clouds, large image files, elevation and bathymetry, and GIS data. These shortcomings in existing data fusion and visualization motivated Makai Ocean Engineering to create a tool called Makai Voyager that could combine and view all relevant scientific data in an interactive global 4D view. The software has applicability in oceanography, marine sciences, offshore oil and geophysical exploration, underwater mining and construction, coastal and environmental engineering, ROV planning and simulation, resource assessment for offshore renewable energy and defense tactical displays.
Design Specifications
Specifications for Makai Voyager were established early in the development process five years ago. Main requirements included the ability to visualize imagery, bathymetry, terrain and true volumetric (voxel) data simultaneously in an interactive georeferenced environment; fuse georeferenced terrain and imagery data from different sources with different datum and projections; and render dynamic isosurfaces and full volumes of grids greater than 5123 voxels, including visualization of scalar and vector (e.g., flow) data. The viewer would also be able to visualize large lidar point clouds; incorporate real-time data from remote sensors; visualize and track 3D objects (e.g., vessels, buoys, biological organisms) using GPS; view georeferenced video; query and analyze data with user tools (e.g., distance measurement, cutting planes, slicing, graphing); and operate at more than 15 to 20 frames per second without a loss in data fidelity on a standard PC. The software also needed to be platform independent (Windows, Macintosh or Linux) and expanded into a Web-based system.
prior to our August 2012 issue, please contact us directly at
firstname.lastname@example.com or +703 524 3136.
Duke J. Hartman is the marketing manager for Makai Ocean Engineering Inc. He received a bachelor's degree with honors in mechanical engineering from the University of Hawai'i at Manoa. His interests are 3D and 4D visualization, ocean thermal energy conversion and seawater air conditioning.
Greg Rocheleau is an ocean and chemical engineer for Makai Ocean Engineering Inc. and has been the primary developer for its OTEC plume model. He received a bachelor's degree in chemical engineering from the University of Colorado at Boulder and a master's in physical oceanography from the University of Hawai'i at Manoa.
Dr. John C. Anderson is the technical lead of the advanced visualization division of Makai Ocean Engineering Inc. He earned a master's and Ph.D. in computer science from the University of California, Davis in 2009. He has authored numerous papers on surface extraction, multivariate analysis and query-driven scientific visualization methods.
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Commute to Downtown New York
Most errands can be accomplished on foot.
Many nearby public transportation options.
Flat as a pancake, excellent bike lanes.
Score Details
This location has a Walk Score of 89 out of 100. This location is Very Walkable so most errands can be accomplished on foot.
This location is a 11 minute walk from the F Queens Blvd Express/ 6 Av Local and the G Brooklyn-Queens Crosstown at the Carroll St stop.
This location is in the Red Hook neighborhood in New York. Nearby parks include The Amazing Garden, Summit Street Community Garden and Human Compass Garden.
Nearby schools include PS 146 Elementary School, Brooklyn School for Collaborative Studies and PS 29 John M Harrigan School.
The closest grocery stores are Aguada Supermarket Inc, Brooklyn General Store and Aiello Dairy.
Nearby coffee shops include Orchard, Kings Coffee and Cafe Adel. Nearby restaurants include Brooklyn Southern, Calexico- Red Hook and Flying Lobster.
This location is near The Amazing Garden, Summit Street Community Garden and Carroll Park.
There are excellent bike lanes and the terrain is flat as a pancake. This location is very bikeable, biking is convenient for most trips. Bike sharing is available from Citi Bike.
Explore how far you can travel by car, bus, bike and foot from this location.
This location has good transit which means many nearby public transportation options. Car sharing is available from Zipcar, RelayRides, Hertz On Demand and Enterprise CarShare.
Rail lines:
F Queens Blvd Express/ 6 Av Local
0.5 mi
G Brooklyn-Queens Crosstown
0.5 mi
4 Lexington Avenue Express
0.9 mi
5 Lexington Avenue Express
0.9 mi
R Broadway Local
1.0 mi
3 7 Avenue Express
1.0 mi
2 7 Avenue Express
1.0 mi
C 8 Avenue Local
1.0 mi
A 8 Avenue Express
1.0 mi
N Broadway Express
1.1 mi
Bus lines:
B61 Park Slope - Downtown Brooklyn
0.0 mi
0.4 mi
B57 Gowanus - Maspeth
0.4 mi
Car shares:
Bike shares:
View all Red Hook apartments on a map.
Popular apartment searches include fireplace, furnished and hardwood floor. View all New York apartments and rentals.
This location is in the Red Hook neighborhood. Red Hook is the 121st most walkable neighborhood in New York with a neighborhood Walk Score of 86.
Moving to New York from another city? View our moving to New York guide.


text:
Signature Service by Pamper Me Please Travel Spa, Washington D.C./Maryland/Virginia
Pamper Me Please uses:Traditional Medicinals Organic Peppermint Tea, Harvest Lights All Natural Soy Peppermint Twist Candles, organic mint leaves, The Body Shop's Peppermint Pedicure Products line: Foot Soak, Refreshing Foot Spray, Foot Mask, Cooling Leg Gel, Pumice Foot Scrub, Foot Lotion or Cooling Intensive Foot Rescue, Peppermint Essential Oil; unscented paraffin wax, base coat, top coat, polish, peppermints.
1. Light a Harvest Lights All Natural Soy Peppermint Twist Candle to set the mood and serve the client peppermint tea.
2. Mix water with a few drops of The Body Shop Peppermint Essential Oil and shake up the mixture. Spray the mist on a warm eye cloth and place over the client's eyes.
3. Add fresh organic mint leaves, The Body Shop Peppermint Mineral Crystal Soak, and a Traditional Medicinals Organic Peppermint tea bag to the foot bath. Soak the client's feet.
4. Spray The Body Shop Peppermint Refreshing Foot Spray on the feet.
5. Prep nails.
6. Apply The Body Shop Cooling Peppermint Foot Mask to feet.
7. Apply The Body Shop Cooling Peppermint Foot and Leg Gel to feet.
8. Exfoliate feet with The Body Shop Peppermint Pumice Foot Scrub.
9. Spray hot towels with the Peppermint Essential Oil mist, wrap them around the client's feet, then remove.
10. Apply The Body Shop Peppermint Foot Lotion or Peppermint Cooling Intensive Foot Rescue (for feet in need of extra moisture).
11. Add Peppermint Essential Oil to unscented paraffin, then dip client's feet in wax, and remove.
12. Polish toenails, and send the client home with a bag of mints.
Price: $90
Alternate Names: Worth a Mint Pedicure, Minty Fresh Pedi, Essential Mint Pedicure
essential oils
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Hidden Gems: Underside Nail Art11 photos
Nail Looks From NYFW F/W2015188 photos
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Mac OS X Tiger For DummiesWiley 2005; US$ 17.59
Mac OS X just keeps getting better! The newest cat in the pack, 10.4 Tiger, has new bells and whistles and terrific updates that make it even easier and more fun to use, which is why you won't want to miss out on the helpful guidance this book has to offer. Written by "Dr. Mac" himself, veteran Macintosh expert Bob LeVitus, Mac OS... more...
Mac OS X Leopard Para DummiesWiley 2009; US$ 17.59
Simplifique las copias de seguridad con Time Machine (Máquina del tiempo) y proteja sus datos La forma divertida y fácil para desatar el poder de las emocionantes funciones de Leopard ¿Quiere ir al fondo de Leopard? Ya sea que usted es un nuevo usuario de Mac o un antiguo usuario entusiasta, esta amigable guía le pone al tanto... more...
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Coast through OS X Mavericks with help from Dr. Mac and For Dummies Ready to make friends with Mavericks? Then, Dr. Mac's your man. Author and longtime Mac guru, Bob "Dr. Mac" LeVitus shares his witty insights and helpful tips in this full-color update to his bestselling OS X guide. You'll learn the basics of working with... more...
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Get the most out of the latest version of OS X Updated and revised for the latest OS X release from Apple, OS X Yosemite For Dummies gives you fun, easy-to-understand coverage of the key features and tools needed to get the most out OS X. Inside, you'll get up and running on OS X basics; customizing your workspace; working with the Dock; finding... more...
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Get to know Snow Leopard and make the most of your Mac Snow Leopard has a few new tricks up its sleeve, so whether you're new to Mac or a longtime Mac-thusiast, Mac expert Bob LeVitus has tips you'll appreciate. Learn how to start up your Mac, get to know the Dock and Finder, work your way through windows and dialogs, and organize and manage files... more...
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Office 2008 for Mac is here, with great new enhancements to allyour favorite office productivity tools. Who better than "Dr.Mac, "Bob LeVitus, to show you how to load and use them all? From choosing the best version for your needs to managing yourlife with your online calendar, Office 2008 For Mac ForDummies covers what you need to know.... more...
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The bestselling Mac guide, updated for the latest Mac OS X andnow in full color! Mac OS X Lion represents a new era in the Mac operating system.This friendly guide is fully updated for the latest Mac OS X andprovides everything new Mac users and users upgrading to Mac OS XLion need to know. A bestseller in previous editions, Mac OS XLion For Dummies... more...
Incredible iPhone Apps For DummiesWiley 2010; US$ 13.59
A full-color directory of must-have iPhone and iPod touchapps! The App Store allows you to browse and download thousands ofapplications that were developed with the iPhone SDK and publishedthrough Apple. The popularity of iPhone and iPod touch apps isexploding and this handy guide helps you sort through the tens ofthousands of available apps so... more...
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Mac OS X Leopard is the new cat in town, and wait until you see allthe tricks it can do! Whether you're new to the Mac or alongtime Mac-thusiast, Mac OS X Leopard For Dummies is thefun and friendly way to have your Leopard purring in no time. While the Mac has built its reputation in part on beinguser-friendly, OS X Leopard has lots of features... more...


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World Championship Poker 2 featuring Howard Lederer lists
Games I've Tested1
A list of games I did QA on.
My games.4
Title says it all... for some games I include a small description. these are all for my fudge load of consoles: http://www.giantbomb.com/profile/mariofreak1/my-consoles/46-56095/ lets just say i am a game collector. if you're wondering how i have...
clubside: Collection
PlayStation 2 Collection4
Ahh the PS2, a game system with some really amazing games. All of the games I own are complete with the case, manual, and everything unless otherwise stated. Some games that I own that are not in the wiki that I need to add: WTA Tour Tennis
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"Victorinox Spectra™ 22-Inch Wide Carry-On in Black" Is Not Available for Sale Online.
We have provided the content below as informational. Please view additional items Customers also viewed.
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- 8-wheel construction provides 360º maneuverability and zero weight-in-hand when rolling upright
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- Integrated Travel Sentry Approved lock allows TSA screeners to open the lock without destroying your luggage and relock it after inspection
- Swiss Tracker Bag Tracking Program will reunite you with your bag for free anywhere in the world should it ever be lost
- Access Lock Combination Recovery Program allows you to register your lock combination on victorinox.com and recover it if forgotten
- Removable ID tag for security and convenience
- Measures 16" W x 9.5" D x 22.5" H
- Weighs 5.7 lb.
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Runny Nose After Touching Vaginal Fluid Worried I Have HIV
Here's a taste of what TheBody.com has to offer on this topic:
Ask the Experts
Another frottage questionDear Dr. Bob:Thank you so much for all the hard work you do with this site. It is very helpful.Now I need your help.I did frottage with an erotic massage parlour girl across her butt crack. At one point my penis went lower than it should have and...
Response from Robert J. Frascino, M.D.
The Robert James Frascino AIDS Foundation...Hi,1. Frottage is not considered to be a risk for HIV transmission. Contact with infected cervical/vaginal fluids, however, does carry some degree of risk.2. No.3. Some STDs can be transmitted by skin-to-skin contact -- HPV/genital warts, Read more »
Thank you from Oberlin Bill!Dr. Bob,I just did the home access test at home and the test result was negative as you suspected! ... Read more »
Oberlin Bill did it again!Hello Doc,Quick question--I did it again. I fingered a girl for about 5-10 minutes and my finger... Read more »
High Anxiety: AIDS Anxiety in the Worried-Wells and Worried-Sicks, Part Two... Read Part One of this blog entry, posted on Sept. 3, 2010. Panic Attack: AIDS Anxiety in HIVers -- "The Worried-Sicks" Recently I received the following post from "Apollo." It graphically demonstrates an Read more »
High Anxiety: AIDS Anxiety in the Worried-Wells and Worried-Sicks, Part One... or on license plates ... hiv 2 research Jun 13, 2006 There are many terms for this type of irrational worrying -- AIDS phobia, AIDS panic, AIDS hysteria, AIDS anxiety, etc. The condition is comprised of three major components: ... Read more »
What Are the Symptoms of HIV and AIDS?... When it comes to the symptoms of HIV/AIDS, there are three major points to keep in mind: There's a big difference between the symptoms of HIV and the symptoms of advanced Read more »
Talking With Your Children About HIV: HIV Awareness for Children...through the following body fluids: Blood (including menstrual blood) Semen ("cum") and other male sexual fluids ("pre-cum") Vaginal fluids Breast milk HIV is not spread through these body fluids: Sweat Tears Saliva (spit) Urine Feces... Read more »
Connect With Others
worried of getting stabbed with hiv in my foot
Posted by worried1234, 3 Replies...really having problem getting on with life right now,i am becoming paranoid,i want to take a test to check for hepatithis and HIV but the windows of 3 months is too long,and my paranoia is making it hard to get on with my everyday life,i dont... Read more »
Positive for Hep C and now worried about HIV
Posted by Worrywart28, 2 Replies...general health and all the std's. I went to see my doctor yesterday. Everything came back fine with the exception of 2 things. My hiv results hadn't come in but she said this is normal because they have to mail that test. Still, that worries me.... Read more »
Long-term HIV and Aids survivors' health worrying
Posted by ScotCharles...KaiserNet January 8, 2008 Some experts and doctors recently have voiced concerns that people who were diagnosed with HIV and Aids in the early years of the epidemic are experiencing "premature[e]" or "disproportionate numbers" of ailments... Read more »
Runny nose?
Posted by Anonymous, 1 Reply...Sorry if this sounds stupid but I know ARS brings around flu like symptoms and was wondering if a runny nose was one of them? Read more »
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Health Care Jobs Forum
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Current Discussions (11) - Start a Discussion
alminwargar in Jacksonville, Florida
Updated 23 months ago
career search in health care field - 4 Replies
Hi, Any career ideas for a 20 year old who likes the health care field but has a low "ick" factor? She wants to have at least some direct contact...
cheris style in Largo, New York
Updated 24 months ago
Tips for Health Care interviews. - 3 Replies
Do you have any tips to help prepare for an upcoming Health Care interview? Are there common interview questions that come up again and again?
Average in Medford, Massachusetts
Updated 35 months ago
Is there a way to get an honest assessment of what healthcare areas have a true shortage? - 1 Reply
I've been searching for jobs and have been told that many professions have shortages of qualified workers. But on coming here it seems many areas...
GoGetter in East Peoria, Illinois
Updated 39 months ago
Top health care skills needed to get the job. - 2 Replies
What are the top 3 traits or skills every health care must have to excel? Can you suggest any tips or insights to develop your health care expertise?
Rhonda in Augusta, Georgia
Updated 44 months ago
Healthcare Field Career Advice - 1 Reply
Hello, I live in Augusta, GA and will most likely need to stay in the area. I currently have a Bachelor's degree in Equine Facility Management but...
lrh in Washington, District of Columbia
Applying to jobs using hospital's online website
I am a current graduate student getting my master's in health service administration. Ihave over 5 years of clinical experience working for a...
saipeople in kingwood, Texas
Updated 75 months ago
Getting a health care job. - 1 Reply
How did you get your start doing health care work, and what career moves did you make to get to your current position? Do you need a particular...
saipeople in kingwood, Texas
Updated 75 months ago
What are typical health care salaries? - 1 Reply
Do some companies pay a lot more for this position than others? What does a top earner make in this field? What skills should you learn to increase...
What do you enjoy most about your Health Care career?
What do you enjoy most about being a Health Care? What do you dislike the most? Is it challenging? Are there many opportunities to learn and...
What are the best health care qualifications and training to get ahead?
What is the best training for becoming a health care? What types of ongoing training or certifications are necessary to be an effective health...
robert throckmorton in Herndon, Virginia
Updated 102 months ago
Boom or bust? - 8 Replies
Are jobs in this industry on the rise? Are there any sub-sectors that are growing? Where are the jobs? Which places have the most health care...
What's great about where you work? If you could change one thing about your job, what would it be? Got a question? Share the best and worst about what you do and where you work by joining a discussion or starting your own.
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