  We propose a new model for estimating the free energy of forming a molecular
cavity in a solvent, by assuming this energy is dominated by the electrostatic
energy associated with creating the static (interface) potential inside the
cavity. The new model approximates the cavity-formation energy as that of a
shell capacitor: the inner, solute-shaped conductor is held at the static
potential, and the outer conductor (at the first solvation shell) is held at
zero potential. Compared to cavity energies computed using free-energy
pertubation with explicit-solvent molecular dynamics, the new model exhibits
surprising accuracy (Mobley test set, RMSE 0.45 kcal/mol). Combined with a
modified continuum model for solute-solvent van der Waals interactions, the
total nonpolar model has RMSE of 0.55 kcal/mol on this test set, which is
remarkable because the two terms largely cancel. The overall nonpolar model has
a small number of physically meaningful parameters and compares favorably to
other published models of nonpolar solvation. Finally, when the proposed
nonpolar model is combined with our solvation-layer interface condition (SLIC)
continuum electrostatic model, which includes asymmetric solvation-shell
response, we predict solvation free energies with an RMS error of 1.35 kcal/mol
relative to experiment, comparable to the RMS error of explicit-solvent FEP
(1.26 kcal/mol). Moreover, all parameters in our model have a clear physical
meaning, and employing reasonable temperature dependencies yields remarkable
correlation with solvation entropies.
