Fast prediction of hydration free energies for SAMPL4 blind test from a classical density functional theory

Abstract

We report the performance of a classical density functional theory (CDFT) in the competition for the solvation free-energy category of the SAMPL4 blind prediction event. The theoretical calculations were carried out with the TIP3P water model and different combinations of solute configurations and molecular force fields. In comparison with the experimental data, the blind test yields an average unsigned error of 2.38 kcal/mol and the root mean square deviation of 2.99 kcal/mol. Whereas these numbers are significantly larger than the best results from explicit-solvent MD simulations, we find that the theoretical performance is sensitive to both the molecular force fields and solute configurations and that a comparable level of accuracy can be achieved by a judicious selection of the solute configurations and the force-field parameters. Most importantly, CDFT reduces the computational cost of MD simulation by almost 3 orders of magnitude, making it very attractive for large-scale hydration free-energy calculations (e.g., screening the aqueous solubility of drug-like molecules).