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

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.