Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design

Abstract

Recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies remains a challenging endeavour, mostly limited to small model cases. We demonstrate accurate absolute binding free energy estimates for 128 pharmaceutically relevant ligands across 7 proteins using a highly parallelizable non-equilibrium method. These calculations also provide detailed physical insight into the structural determinants of binding, identifying subtle rotamer rearrangements between protein apo and holo states that are crucial for binding. The challenge behind absolute binding free energy calculations stems in large part from the need to explicitly account for the protein's apo state. In this work we present several approaches to obtain apo state ensembles, including a novel rigorous method to generate protein-ligand ensembles for the ligand in its decoupled state. Altogether, we present an effective open-source protocol for prospective application in drug discovery.