One-Step Perturbation Methods for Solvation Free Energies of Polar Solutes

Abstract

The one-step perturbation approach to free energy calculations permits the calculation of relative free energies for a number of end states from a single simulation of a carefully chosen reference state. This approach has successfully been used for the calculation of relative and absolute solvation free energies of nonpolar solutes in water, as well as relative binding free energies for a family of nonpolar protein ligands. We have investigated several possible approaches to extend one-step perturbation methods to also obtain accurate solvation free energies of polar species. A “soft dipole” reference state permits the determination of accurate relative solvation free energies for polar solutes (average unsigned error < 2.0 kJ/mol) but does not yield accurate absolute solvation free energies. However, contrary to expectations, simulations of a neutral reference state even yield accurate (average unsigned error < 2.9 kJ/mol) absolute solvation free energies for polar solutes when translational and rotational sampling of the solute is included. In general, the choice of an appropriate reference state for one-step perturbation is a challenge because of complex many-body effects. Nonetheless, the one-step perturbation method combined with an unphysical reference state yields accurate free energy estimates with an efficiency several times greater than traditional approaches.