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Hydrophobic interactions drive the binding of nonpolar ligands to the oily pockets of proteins and supramolecular species in aqueous solution. As such, the wetting of host pockets is expected to play a critical role in determining the thermodynamics of guest binding. Here we use molecular simulations to examine the impact of pressure on the wetting and dewetting of the nonpolar pockets of a series of deep-cavity cavitands in water. The portals to the cavitand pockets are functionalized with both nonpolar (methyl) and polar (hydroxyl) groups oriented pointing either upward or inward toward the pocket. We find wetting of the pocket is favored by the hydroxyl groups and dewetting is favored by the methyl groups. The distribution of waters in the pocket is found to exhibit a two-state-like equilibrium between wet and dry states with a free energy barrier between the two states. Moreover, we demonstrate that the pocket hydration of the cavitands can be collapsed onto a unified adsorption isotherm by assuming the effective pressures within each cavitand pocket differ by a shift pressure that depends on the chemical identity and number of functional groups placed about the portal. These observations support the development of a twostate capillary evaporation model that accurately describes the equilibrium between states and naturally gives rise to the effective shift pressures observed from simulation. This work demonstrates that the hydration of host pockets can be tuned following simple design rules that in turn are expected to impact the thermodynamics of guest complexation. 

The field of polymer membrane design is primarily based on empirical observation, which limits discovery of new materials optimized for separating a given gas pair. Instead of relying on exhaustive experimental investigations, we trained a machine learning (ML) algorithm, using a topological, path-based hash of the polymer repeating unit. We used a limited set of experimental gas permeability data for six different gases in ~700 polymeric constructs that have been measured to date to predict the gas-separation behavior of over 11,000 homopolymers not previously tested for these properties. To test the algorithm’s accuracy, we synthesized two of the most promising polymer membranes predicted by this approach and found that they exceeded the upper bound for CO 2 /CH 4 separation performance. This ML technique, which is trained using a relatively small body of experimental data (and no simulation data), evidently represents an innovative means of exploring the vast phase space available for polymer membrane design. 

There are many open questions regarding the hydration of solvent-exposed, non-polar tracts and pockets in proteins. Although water is predicted to de-wet purely repulsive surfaces and evacuate crevices, the extent of de-wetting is unclear when ubiquitous van der Waals interactions are in play. The structural simplicity of synthetic supramolecular hosts imbues them with considerable potential to address this issue. To this end, here we detail a combination of densimetry and molecular dynamics simulations of three cavitands, coupled with calorimetric studies of their complexes with short-chain carboxylates. Our results reveal the range of wettability possible within the ostensibly identical cavitand pockets — which differ only in the presence/position of the methyl groups that encircle the portal to their non-polar pockets. The results demonstrate the ability of macrocycles to template water cavitation within their binding sites and show how the orientation of methyl groups can trigger the drying of non-polar pockets in liquid water, suggesting new avenues to control guest complexation.