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The Alchemical Transfer Method (ATM) is herein validated against the relativebinding free energies of a diverse set of protein-ligand complexes. We employeda streamlined setup workflow, a bespoke force field, and the AToM-OpenMMsoftware to compute the relative binding free energies (RBFE) of the benchmarkset prepared by Schindler and collaborators at Merck KGaA. This benchmark setincludes examples of standard small R-group ligand modifications as well asmore challenging scenarios, such as large R-group changes, scaffold hopping,formal charge changes, and charge-shifting transformations. The novelcoordinate perturbation scheme and a dual-topology approach of ATM address someof the challenges of single-topology alchemical relative binding free energymethods. Specifically, ATM eliminates the need for splitting electrostatic andLennard-Jones interactions, atom mapping, defining ligand regions, andpost-corrections for charge-changing perturbations. Thus, ATM is simpler andmore broadly applicable than conventional alchemical methods, especially forscaffold-hopping and charge-changing transformations. Here, we performed wellover 500 relative binding free energy calculations for eight protein targetsand found that ATM achieves accuracy comparable to existing state-of-the-artmethods, albeit with larger statistical fluctuations. We discuss insights intospecific strengths and weaknesses of the ATM method that will inform futuredeployments. This study confirms that ATM is applicable as a production toolfor relative binding free energy (RBFE) predictions across a wide range ofperturbation types within a unified, open-source framework.

Performance and Analysis of the Alchemical Transfer Method for Binding Free Energy Predictions of Diverse Ligands