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 two-state 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 hydrophobic effect is an umbrella term encompassing a number of solvation phenomena associated with solutions of nonpolar species in water, including the following: a meager solubility opposed by entropy at room temperature; large positive hydration heat capacities; positive shifts in the temperature of maximum density of aqueous mixtures; increases in the speed of sound of dilute aqueous mixtures; and negative volumes of association between interacting solutes. Here we present a molecular simulation study of nonpolar gas hydration over the temperature range 273.15–373.15 K and a pressure range −500 to 1000 bar to investigate the interrelationships between distinct hydrophobic phenomena. We develop a new free energy correlation for the solute chemical potentials founded on the Tait equation description of the equation-of-state of liquid water. This analytical correlation is shown to provide a quantitatively accurate description of nonpolar gas hydration over the entire range of thermodynamic state points simulated, with an error of ∼0.02 k B T or lower in the fitted chemical potentials. Our simulations and the correlation accurately reproduce many of the available experimental results for the hydration of the solutes examined here. Moreover, the correlation reproduces the characteristic entropies of hydration, temperature dependence of the hydration heat capacity, perturbations in the temperature of maximum density, and changes in the speed of sound. While negative volumes of association result from pairwise interactions in solution, beyond the limits of our simulations performed at infinite dilution, we discuss how our correlation could be supplemented with second virial coefficient information to expand to finite concentrations. In total, this work demonstrates that many distinct phenomena associated with the hydrophobic effect can be captured within a single thermodynamically consistent correlation for solute hydration free energies.