  The Alchemical Transfer Method (ATM) for the calculation of standard binding
free energies of non-covalent molecular complexes is presented. The method is
based on a coordinate displacement perturbation of the ligand between the
receptor binding site and the explicit solvent bulk, and a thermodynamic cycle
connected by a symmetric intermediate in which the ligand interacts with the
receptor and solvent environments with equal strength. While the approach is
alchemical, the implementation of ATM is as straightforward as for physical
pathway methods of binding. The method is applicable in principle with any
force field, it does not require splitting the alchemical transformations into
electrostatic and non-electrostatic steps, and it does not require soft-core
pair potentials. We have implemented ATM as a freely available and open-source
plugin of the OpenMM molecular dynamics library. The method and its
implementation are validated on the SAMPL6 SAMPLing host-guest benchmark set.
The work paves the way to streamlined alchemical relative and absolute binding
free energy implementations on many molecular simulation packages and with
arbitrary energy functions including polarizable, quantum-mechanical, and
artificial neural network potentials.
