Alchemical Grid Dock (AlGDock): Binding Free Energy Calculations between Flexible Ligands and Rigid Receptors

Alchemical Grid Dock (AlGDock) is open-source software designed to compute the binding potential of mean force—the binding free energy between a flexible ligand and a rigid receptor—for a small organic ligand and a biological macromolecule. Multiple BPMFs can be used to rigorously compute binding affinities between flexible partners. AlGDock uses replica exchange between thermodynamic states at different temperatures and receptor–ligand interaction strengths. Receptor–ligand interaction energies are represented by interpolating precomputed grids. Thermodynamic states are adaptively initialized and adjusted on-the-fly to maintain adequate replica exchange rates. In demonstrative calculations, when the bound ligand is treated as fully solvated, AlGDock estimates BPMFs with a precision within 4 kT in 65% and within 8 kT for 91% of systems. It correctly identifies the native binding pose in 83% of simulations. Performance is sometimes limited by subtle differences in the important configuration space of sampled and targeted thermodynamic states. © 2019 Wiley Periodicals, Inc.