Alchemical Transfer Approach to Absolute Binding Free Energy Estimation

Abstract: 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.