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Rapid, Accurate, Precise, and Reliable Relative Free Energy Prediction Using Ensemble Based Thermodynamic Integration

Bhati, AP; Wan, S; Wright, DW; Coveney, PV; (2017) Rapid, Accurate, Precise, and Reliable Relative Free Energy Prediction Using Ensemble Based Thermodynamic Integration. Journal of Chemical Theory and Computation , 13 (1) pp. 210-222. 10.1021/acs.jctc.6b00979. Green open access

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Abstract

The accurate prediction of the binding affinities of ligands to proteins is a major goal in drug discovery and personalized medicine. The time taken to make such predictions is of similar importance to their accuracy, precision, and reliability. In the past few years, an ensemble based molecular dynamics approach has been proposed that provides a route to reliable predictions of free energies based on the molecular mechanics Poisson-Boltzmann surface area method which meets the requirements of speed, accuracy, precision, and reliability. Here, we describe an equivalent methodology based on thermodynamic integration to substantially improve the speed, accuracy, precision, and reliability of calculated relative binding free energies. We report the performance of the method when applied to a diverse set of protein targets and ligands. The results are in very good agreement with experimental data (90% of calculations agree to within 1 kcal/mol), while the method is reproducible by construction. Statistical uncertainties of the order of 0.5 kcal/mol or less are achieved. We present a systematic account of how the uncertainty in the predictions may be estimated.

Type: Article
Title: Rapid, Accurate, Precise, and Reliable Relative Free Energy Prediction Using Ensemble Based Thermodynamic Integration
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jctc.6b00979
Publisher version: http://dx.doi.org/10.1021/acs.jctc.6b00979
Language: English
Additional information: This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1534399
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