The characteristic structure of PROTACs, two small molecules connected by a flexible linker, lends itself to the formation of intramolecular hydrogen bonds (IMHBs). This important feature allows for polar atoms to be shuttled across the lipophilic cell membrane. It is difficult to determine the presence of IMHBs by inspecting the 2D chemical structure alone. However, measuring the lipophilic permeability efficiency (LPE) of matched pairs can indicate differences in the number of exposed HBDs. LPE is a metric that balances aqueous solubility (calculated ALogP) and membrane partitioning (experimental LogD(dec/w)) to determine the efficiency with which a compound crosses a membrane at a given lipophilicity. Similar to the previously developed DLogP metric, LPE is particularly valuable in determining differences in solventexposed HBDs between compounds. Compounds with similar LPE values are likely to have the same number of solvent-exposed HBDs, while a DLPE of 1.8 suggests the difference of a single exposed HBD (compounds with higher LPE values have fewer exposed HBDs). For the majority of the liposcan compound pairs (2 -6 vs. 9 -13, respectively), the ester compounds had higher LPEs than their counterpart amide compounds (Table ). The DLPEs of between 1.1 and 1.8 suggest that the additional HBD in the amide compounds is partially to fully solvent-exposed. Interestingly, the amide compounds with an ether oxygen five atoms away from the amide -NH had similarly low DLPEs (cf. 1 vs. 8, 15 vs. 18, and 17 vs. 20, Table ). Consistent with previous work, this suggests that the amide -NH is making an IMHB with the ether oxygen in the PEG linker (15 and 17) or the OMe ether oxygen of a POI ligand mimic (1). These results are also consistent with recent work from Kihlberg, et al., who used NMR to show IMHB between PROTAC warheads and the oxygen atoms in their PEG linkers. Therefore, while ester bonds and alkyl linkers are better for permeability, when used in combination, a PEG linker and amide bond could be used to shield the polarity of important HBDs that are crucial to the bioactivity or solubility of the overall molecule.