Journal
JOURNAL OF COMPUTATIONAL CHEMISTRY
Volume 41, Issue 7, Pages 715-730Publisher
WILEY
DOI: 10.1002/jcc.26036
Keywords
protein-ligand; noncovalent binding free energy; implicit ligand theory; thermodynamic length; replica exchange
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Funding
- National Science Foundation
- U.S. Department of Energy's Office of Science
- National Science Foundation [ACI-1548562]
- NIH [2P50 GM067082-06-10, 1R15 GM114781]
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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. (c) 2019 Wiley Periodicals, Inc.
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