  We present an extension of Alchemical Transfer Method (ATM) for the
estimation of relative binding free energies of molecular complexes applicable
to conventional as well as scaffold-hopping alchemical transformations. The
method, named ATM-RBFE, implemented in the free and open-source OpenMM
molecular simulation package, aims to provide a simpler and more generally
applicable route to the calculation of relative binding free energies than is
currently available. The method is based on sound statistical mechanics theory
and a novel coordinate perturbation scheme designed to swap the positions of a
pair of ligands such that one is transferred from the bulk solvent to the
receptor binding site while the other moves simultaneously in the opposite
direction. The calculation is conducted directly using a single solvent box
prepared using conventional setup tools, without splitting of electrostatic and
non-electrostatic transformations, and without pairwise soft-core potentials.
ATM-RBFE is validated here against the absolute binding free energies of the
SAMPL8 GDCC host-guest benchmark set and against a benchmark set of estrogen
receptor $\alpha$ complexes. In each case, the method yields self-consistent
and converged relative binding free energy estimates in agreement with absolute
binding free energies, reference literature values as well as experimental
measurements.
