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

TL;DR

AlGDock is an open-source tool that accurately computes binding free energies between flexible ligands and rigid receptors using replica exchange and precomputed interaction grids.

Contribution

It introduces a novel approach combining replica exchange, adaptive thermodynamic states, and grid interpolation for efficient binding free energy calculations.

Findings

Estimates BPMFs within 4 kT in 65% of cases

Correctly identifies native binding pose in 83% of simulations

Performance limited by subtle configuration space differences

Abstract

Alchemical Grid Dock (AlGDock) is open-source software designed to compute the binding potential of mean force (BPMF) - 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 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.