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

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.

53 pages, 12 figures, 4 supplemental figures

References in corpus (4)

• The NumPy array: a structure for efficient numerical computation
• Replica exchange and expanded ensemble simulations as Gibbs sampling: Simple improvements for enhanced mixing
• Implicit Ligand Theory: Rigorous Binding Free Energies and Thermodynamic Expectations from Molecular Docking
• Using the Fast Fourier Transform in Binding Free Energy Calculations

Cited by in corpus (3)

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