Large-scale Protein-ligand Binding Free Energy Calculations Via Implicit Ligand Theory

11:00 a.m.

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David Minh (Robert E. Frey, Jr. Endowed Chair in Chemistry, Associate Professor, Department of Chemistry, Associate Director, Center for Interdisciplinary Scientific Computation, Illinois Institute of Technology)

Implicit ligand theory (ILT) provides a way to calculate noncovalent binding free energies via an exponential average of the binding potential of mean force (BPMF) - the binding free energy between a flexible ligand and rigid receptor (1, 2). Receptor configurations must be drawn from or reweighed to an apo (1) or holo (2) ensemble. Computing binding free energies based on multiple BPMFs has several advantages over simulations with a flexible receptor: the ensemble of receptor configurations can be thoroughly sampled once and recycled for a large chemical library of ligands; accuracy can be progressively increased by computing BPMFs for more receptor snapshots (3); the task of computing multiple BPMFs is trivially parallel; and BPMFs can be much faster to compute and more scalable than binding free energies to flexible proteins. In the last several years, my group derived ILT (1, 2), developed tools to compute protein- ligand BPMFs based on replica exchange (4) and the fast Fourier transform (5), and applied them to the binding of small hydrophobic molecules to T4 lysozyme (3) and in the D3R grand challenge (6). Through these studies we have established that for simple ligands and binding sites, ILT-based calculations can reproduce results of more computationally expensive approaches. We are working on making BPMF calculation more efficient so that they can be applied to larger ligands and chemical libraries. In another application of these calculations, our preliminary data indicate that BPMFs significantly outperform interaction energies in classifying agonists and antagonists of the estrogen receptor.

1. Minh, D. D. L. (2012) Implicit ligand theory: Rigorous binding free energies and thermodynamic expectations from molecular docking. J. Chem. Phys. 137, 104106
2. Nguyen, T. H., and Minh, D. D. L. (2018) Implicit ligand theory for relative binding free energies. J. Chem. Phys. 148, 104114
3. Xie, B., Nguyen, T. H., and Minh, D. D. L. (2017) Absolute Binding Free Energies between T4 Lysozyme and 141 Small Molecules: Calculations Based on Multiple Rigid Receptor Configurations. J. Chem. Theory Comput. 13, 2930–2944
4. Minh, D. D. L. (2019) Alchemical Grid Dock (AlGDock): Binding Free Energy Calculations between Flexible Ligands and Rigid Receptors. J. Comput. Chem. https://doi.org/10.1002/jcc.26036  
5. Nguyen, T. H., Zhou, H.-X., and Minh, D. D. L. (2018) Using the Fast Fourier Transform in Binding Free Energy Calculations. J. Comput. Chem. 39, 621–636
6. Xie, B., and Minh, D. D. L. (2019) Alchemical Grid Dock (AlGDock) calculations in the D3R Grand Challenge 3. J. Comput. Aided Mol. Des. 33, 61–69