Toward high-throughput predictions of the hydration free energies of small organic molecules from first principles

Abstract

In this work we examine a multiscale procedure for predicting the solvation free energies of small organic molecules in liquid water at ambient conditions. The experimental database consists of thermodynamic data for 2583 neutral organic molecules, one of the largest sets available in the molecular modeling community. Using the extensive experimental data for hydration free energies as a benchmark, we find that the theoretical predictions are sensitive not only to water models but also to quantum-mechanical calculations for determining the molecular configurations and the atomic charges of solute molecules, and to the assignment of the non-bonded force-field parameters for different organic functional groups. Considering the computational cost of multiscale modeling for large-scale free-energy calculations from first principles, we maintain that the classical density functional theory provides a valuable alternate to conventional molecular simulation methods. The theoretical procedure will be important for future development of semi-empirical force fields and, in particular, for applications of multiscale modeling methods to practical problems that require high-throughput free-energy calculations.