A displaced-solvent functional analysis of model hydrophobic enclosures.

Calculation of protein-ligand binding affinities continues to be a hotbed of research. Although many techniques for computing protein-ligand binding affinities have been introduced--ranging from computationally very expensive approaches, such as free energy perturbation (FEP) theory; to more approximate techniques, such as empirically derived scoring functions, which, although computationally efficient, lack a clear theoretical basis--there remains pressing need for more robust approaches. A recently introduced technique, the displaced-solvent functional (DSF) method, was developed to bridge the gap between the high accuracy of FEP and the computational efficiency of empirically derived scoring functions. In order to develop a set of reference data to test the DSF theory for calculating absolute protein-ligand binding affinities, we have pursued FEP theory calculations of the binding free energies of a methane ligand with 13 different model hydrophobic enclosures of varying hydrophobicity. The binding free energies of the methane ligand with the various hydrophobic enclosures were then recomputed by DSF theory and compared with the FEP reference data. We find that the DSF theory, which relies on no empirically tuned parameters, shows excellent quantitative agreement with the FEP. We also explored the ability of buried solvent accessible surface area and buried molecular surface area models to describe the relevant physics, and find the buried molecular surface area model to offer superior performance over this dataset.