Binding Selectivity Analysis from Alchemical Receptor Hopping and Ligand Swapping Free Energy Calculations

We present receptor-hopping and ligand-swapping free energy estimation protocols based on the Alchemical Transfer Method (ATM) to model the binding selectivity of a set of ligands to two arbitrary receptors. The receptor-hopping protocol, where a ligand is alchemically transferred from one receptor to another in one simulation, directly yields the ligand's binding selectivity free energy for the two receptors, which is the difference between the two binding free energies. In the ligand-swapping protocol, the first ligand of a pair is transferred from one receptor to another while the second ligand is simultaneously transferred in the opposite direction. The ligand-swapping free energy yields the differences in binding selectivity free energies of a set of ligands, which, when combined using a generalized DiffNet algorithm, yield the binding selectivity free energies of the ligands. We test these novel algorithms on host-guest systems and show that they yield results values in good agreement with experimental data and consistent with differences of absolute and relative binding free energies obtained by conventional methods. The novel algorithms presented in this work are a first step in developing streamlined and computationally efficient protocols for modeling ligand selectivity across protein receptors with potentially low sequence identity in structure-based drug discovery.