Ensemble-Based Replica Exchange Alchemical Free Energy Methods: The Effect of Protein Mutations on Inhibitor Binding
Abstract
According to the article, the accurate prediction of the binding affinity changes of drugs caused by protein mutations is a major goal in clinical personalized medicine. We have developed an ensemble-based free energy approach called thermodynamic integration with enhanced sampling (TIES), which yields accurate, precise, and reproducible binding affinities. TIES has been shown to perform well for predictions of free energy differences of congeneric ligands to a wide range of target proteins. We have recently introduced variants of TIES, which incorporate the enhanced sampling technique REST2 (replica exchange with solute tempering) and the free energy estimator MBAR (Bennett acceptance ratio). Here we further extend the TIES methodology to study relative binding affinities caused by protein mutations when bound to a ligand, a variant which we call TIES-PM. We apply TIES-PM to fibroblast growth factor receptor 3 (FGFR3) to investigate binding free energy changes upon protein mutations. The results show that TIES-PM with REST2 successfully captures a large conformational change and generates correct free energy differences caused by a gatekeeper mutation located in the binding pocket. Simulations without REST2 fail to overcome the energy barrier between the conformations, and hence the results are highly sensitive to the initial structures. We alsomore »
- Authors:
-
[1];
[1]
- Univ. College London (UCL) (United Kingdom). Dept. of Chemistry, Centre for Computational Science
- Publication Date:
- Research Org.:
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); UT-Battelle LLC/ORNL, Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR); Qatar National Research Fund (QNRF); National Science Foundation (NSF); European Commission (EC)
- OSTI Identifier:
- 1565743
- Grant/Contract Number:
- AC05-00OR22725; 7-1083-1-191; NSF-1713749; 671564; 675451
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Chemical Theory and Computation
- Additional Journal Information:
- Journal Volume: 15; Journal Issue: 2; Journal ID: ISSN 1549-9618
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Chemistry; Physics; Free energy; Genetics; Inhibitors; Conformation; Screening assays
Citation Formats
Bhati, Agastya P., Wan, Shunzhou, and Coveney, Peter V. Ensemble-Based Replica Exchange Alchemical Free Energy Methods: The Effect of Protein Mutations on Inhibitor Binding. United States: N. p., 2018.
Web. doi:10.1021/acs.jctc.8b01118.
Bhati, Agastya P., Wan, Shunzhou, & Coveney, Peter V. Ensemble-Based Replica Exchange Alchemical Free Energy Methods: The Effect of Protein Mutations on Inhibitor Binding. United States. https://doi.org/10.1021/acs.jctc.8b01118
Bhati, Agastya P., Wan, Shunzhou, and Coveney, Peter V. Fri .
"Ensemble-Based Replica Exchange Alchemical Free Energy Methods: The Effect of Protein Mutations on Inhibitor Binding". United States. https://doi.org/10.1021/acs.jctc.8b01118. https://www.osti.gov/servlets/purl/1565743.
@article{osti_1565743,
title = {Ensemble-Based Replica Exchange Alchemical Free Energy Methods: The Effect of Protein Mutations on Inhibitor Binding},
author = {Bhati, Agastya P. and Wan, Shunzhou and Coveney, Peter V.},
abstractNote = {According to the article, the accurate prediction of the binding affinity changes of drugs caused by protein mutations is a major goal in clinical personalized medicine. We have developed an ensemble-based free energy approach called thermodynamic integration with enhanced sampling (TIES), which yields accurate, precise, and reproducible binding affinities. TIES has been shown to perform well for predictions of free energy differences of congeneric ligands to a wide range of target proteins. We have recently introduced variants of TIES, which incorporate the enhanced sampling technique REST2 (replica exchange with solute tempering) and the free energy estimator MBAR (Bennett acceptance ratio). Here we further extend the TIES methodology to study relative binding affinities caused by protein mutations when bound to a ligand, a variant which we call TIES-PM. We apply TIES-PM to fibroblast growth factor receptor 3 (FGFR3) to investigate binding free energy changes upon protein mutations. The results show that TIES-PM with REST2 successfully captures a large conformational change and generates correct free energy differences caused by a gatekeeper mutation located in the binding pocket. Simulations without REST2 fail to overcome the energy barrier between the conformations, and hence the results are highly sensitive to the initial structures. We also discuss situations where REST2 does not improve the accuracy of predictions.},
doi = {10.1021/acs.jctc.8b01118},
journal = {Journal of Chemical Theory and Computation},
number = 2,
volume = 15,
place = {United States},
year = {Fri Dec 28 00:00:00 EST 2018},
month = {Fri Dec 28 00:00:00 EST 2018}
}
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Works referencing / citing this record:
Accuracy and Precision of Alchemical Relative Free Energy Predictions with and without Replica‐Exchange
journal, November 2019
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