The Alchemical Transfer Method (ATM) is herein validated against the relative
binding free energies of a diverse set of protein-ligand complexes. We employed
a streamlined setup workflow, a bespoke force field, and the AToM-OpenMM
software to compute the relative binding free energies (RBFE) of the benchmark
set prepared by Schindler and collaborators at Merck KGaA. This benchmark set
includes examples of standard small R-group ligand modifications as well as
more challenging scenarios, such as large R-group changes, scaffold hopping,
formal charge changes, and charge-shifting transformations. The novel
coordinate perturbation scheme and a dual-topology approach of ATM address some
of the challenges of single-topology alchemical relative binding free energy
methods. Specifically, ATM eliminates the need for splitting electrostatic and
Lennard-Jones interactions, atom mapping, defining ligand regions, and
post-corrections for charge-changing perturbations. Thus, ATM is simpler and
more broadly applicable than conventional alchemical methods, especially for
scaffold-hopping and charge-changing transformations. Here, we performed well
over 500 relative binding free energy calculations for eight protein targets
and found that ATM achieves accuracy comparable to existing state-of-the-art
methods, albeit with larger statistical fluctuations. We discuss insights into
specific strengths and weaknesses of the ATM method that will inform future
deployments. This study confirms that ATM is applicable as a production tool
for relative binding free energy (RBFE) predictions across a wide range of
perturbation types within a unified, open-source framework