A Non-Alchemical Absolute Binding Free Energy Framework for Small Molecule Drugs

Abstract

A fully physical, non-alchemical framework is presented for absolute binding free energy (ABFE) calculations for protein-ligand complexes. Incorporation of a regularization potential eliminates unphysical artifacts and provides several key advantages: no endpoint catastrophes, fast convergence, robust performance for charged and neutral ligands, and rapid upfront verification. Validated on 30 diverse systems, the method improves predictive accuracy by 15.6% and numerical stability by 17.1% over leading alchemical approaches. This non-alchemical ABFE framework can be a potentially accurate and robust tool, carrying a potential for future computer aided small-molecule drug design.