On the nonpolar hydration free energy of proteins: surface area and continuum solvent models for the solute-solvent interaction energy.

Implicit solvent hydration free energy models are an important component of most modern computational methods aimed at protein structure prediction, binding affinity prediction, and modeling of conformational equilibria. The nonpolar component of the hydration free energy, consisting of a repulsive cavity term and an attractive van der Waals solute−solvent interaction term, is often modeled using estimators based on the solvent exposed solute surface area. In this paper, we analyze the accuracy of linear surface area models for predicting the van der Waals solute−solvent interaction energies of native and non-native protein conformations, peptides and small molecules, and the desolvation penalty of protein−protein and protein−ligand binding complexes. The target values are obtained from explicit solvent simulations and from a continuum solvent van der Waals interaction energy model. The results indicate that the standard surface area model, while useful on a coarse-grained scale, may not be accurate or tr...