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Uncertainty Quantification in Alchemical Free Energy Methods

Bhati, AP; Wan, S; Hu, Y; Sherborne, B; Coveney, PV; (2018) Uncertainty Quantification in Alchemical Free Energy Methods. Journal of Chemical Theory and Computation 10.1021/acs.jctc.7b01143. (In press). Green open access

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Abstract

Alchemical free energy methods have gained much importance recently from several reports of improved ligand-protein binding affinity predictions based on their implementation using molecular dynamics simulations. A large number of variants of such methods implementing different accelerated sampling techniques and free energy estimators are available, each claimed to be better than the others in its own way. However, the key features of reproducibility and quantification of associated uncertainties in such methods have barely been discussed. Here, we apply a systematic protocol for uncertainty quantification to a number of popular alchemical free energy methods, covering both absolute and relative free energy predictions. We show that a reliable measure of error estimation is provided by ensemble simulation-an ensemble of independent MD simulations-which applies irrespective of the free energy method. The need to use ensemble methods is fundamental and holds regardless of the duration of time of the molecular dynamics simulations performed.

Type: Article
Title: Uncertainty Quantification in Alchemical Free Energy Methods
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jctc.7b01143
Publisher version: http://doi.org/10.1021/acs.jctc.7b01143
Language: English
Additional information: Copyright © 2018 American Chemical Society. 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.
URI: http://discovery.ucl.ac.uk/id/eprint/10048471
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