Divide-and-Conquer ABFE: Improving Free Energy Calculations by Enhancing Water Sampling.

Abstract

Free energy perturbation (FEP) is a promising method for accurately predicting molecular interactions, widely applied in fields such as drug design, materials science, and catalysis. However, FEP calculations, particularly those in aqueous environments, often suffer from convergence issues due to insufficient sampling of water molecules. These challenges are particularly critical in solvation-related free energy calculations, such as small molecule-protein binding, interface interactions, and molecular adsorption on surfaces. To address these limitations, we present the divide-and-conquer absolute binding free energy (DC-ABFE) method. By partitioning the ligand or molecule into atomic groups and sequentially decoupling their van der Waals interactions, DC-ABFE improves water re-entry sampling, enhances phase-space overlap, and significantly enhances the convergence of free energy calculations. Our benchmark demonstrates that DC-ABFE achieves more reproducible and reliable binding free energy predictions compared to traditional FEP methods. DC-ABFE is applicable to a range of free energy calculations involving solvation effects. Additionally, this method establishes a stronger foundation for precise drug screening, offering a more robust tool for predicting binding affinities in drug discovery.