Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field.

TLDR: This work uses explicit solvent molecular dynamics free energy perturbation to predict the absolute solvation free energies of a set of 239 small molecules, spanning diverse chemical functional groups commonly found in drugs and drug-like molecules and shows that predictions can be improved by using a semiempirical charge assignment method with an implicit bond charge correction.

Abstract: The accurate prediction of protein−ligand binding free energies is a primary objective in computer-aided drug design. The solvation free energy of a small molecule provides a surrogate to the desolvation of the ligand in the thermodynamic process of protein−ligand binding. Here, we use explicit solvent molecular dynamics free energy perturbation to predict the absolute solvation free energies of a set of 239 small molecules, spanning diverse chemical functional groups commonly found in drugs and drug-like molecules. We also compare the performance of absolute solvation free energies obtained using the OPLS_2005 force field with two other commonly used small molecule force fields—general AMBER force field (GAFF) with AM1-BCC charges and CHARMm-MSI with CHelpG charges. Using the OPLS_2005 force field, we obtain high correlation with experimental solvation free energies (R2 = 0.94) and low average unsigned errors for a majority of the functional groups compared to AM1-BCC/GAFF or CHelpG/CHARMm-MSI. However, ...