Relative Binding Free Energy Estimation of Congeneric Ligands and Macromolecular Mutants with the Alchemical Transfer Method with Coordinate Swapping.

We present the Alchemical Transfer with Coordinate Swapping (ATS) method to enable the calculation of the relative binding free energies between large congeneric ligands and single-point mutant peptides to protein receptors with the Alchemical Transfer Method (ATM) framework. Similarly to ATM, the new method implements the alchemical transformation as a coordinate transformation and works with any unmodified force fields and standard chemical topologies. Unlike ATM, which transfers whole ligands in and out of the receptor binding site, ATS limits the magnitude of the alchemical perturbation by transferring only the portion of the molecules that differ between the bound and unbound ligands. The common region of the two ligands, which can be arbitrarily large, is unchanged and does not contribute to the magnitude and statistical fluctuations of the perturbation energy. Internally, the coordinates of the atoms of the common regions are swapped to maintain the integrity of the covalent bonding data structures of the OpenMM molecular dynamics engine. The work successfully validates the method on protein-ligand and protein-peptide RBFE benchmarks. This advance paves the road for the application of the relative binding free energy Alchemical Transfer Method protocol to study the effect of protein and nucleic acid mutations on the binding affinity and specificity of macromolecular complexes.