Continuum solvent modeling of nonpolar solvation: Improvement by separating surface area dependent cavity and dispersion contributions

Continuum models are frequently used to calculate hydration properties of organic and biomolecules and to estimate its dependence on conformation and association. Often a single surface tension parameter has been used to estimate nonpolar solvation contributions from the solvent accessible surface of a molecule. The assumption of a uniform surface tension parameter is based on the observation that for linear alkanes free energies of hydration (vacuum to water transfer free energies) increase (approximately) linearly with the solvent accessible surface area (SAS). However, this correlation for example does not hold for the vacuum to water transfer of cyclic alkanes. The transfer of a nonpolar solute from vacuum to water can be formally split into a contribution due to cavity formation which involves a redistribution and reordering of water molecules and changes in water-water interaction and second van der Waals (dispersion) interactions between solute and water. In the present study, the solute solvent dispersion contribution has been calculated using a surface integral continuum approach (Floris, F.; Tomasi, J. J. Comput. Chem. 1989, 10, 616-627). Combined with a cavity contribution that has been assumed to be proportional to the solvent accessible surface area calculated hydration free energies for linear, branched and cyclic alkanes are in significantly better agreement with experiment than using a pure SAS model. In addition, the calculated changes of hydration free energies upon alkane conformational changes agree much better with results of explicit solvent simulations compared to a model that employs a single surface tension parameter.