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

TLDR

The solvation free energy of a small molecule serves as a surrogate for ligand desolvation in protein–ligand binding thermodynamics. The study aims to accurately predict protein–ligand binding free energies by using explicit‑solvent molecular dynamics free‑energy perturbation to compute absolute solvation free energies for 239 diverse small molecules. Absolute solvation free energies were calculated via explicit‑solvent MD free‑energy perturbation and compared across the OPLS_2005 force field with GAFF/AM1‑BCC and CHARMm‑MSI/CHelpG force fields. OPLS_2005 achieves a high correlation (R² = 0.94) with experimental solvation free energies and low unsigned errors for most functional groups, though it incurs errors over 1.3 kcal/mol for some polar compounds, which can be mitigated by a semi‑empirical charge assignment with 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, OPLS_2005 has errors of over 1.3 kcal/mol for certain classes of polar compounds. We show that predictions on these compound classes can be improved by using a semiempirical charge assignment method with an implicit bond charge correction.