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.
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