Journal
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 14, Issue 6, Pages 2867-2880Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jctc.7b01143
Keywords
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Funding
- EPSRC [EP/I017909/1]
- Qatar National Research Fund [7-1083-1-191]
- MRC Medical Bioinformatics project [MR/L016311/1]
- EU H2020 projects ComPat [671564]
- CompBioMed [675451]
- NSF [NSF 1713749]
- UCL Provost
- Office of Science and Technology through EPSRC's High-End Computing Programme
- Overseas Research Scholarship from UCL
- Inlaks Scholarship from the Inlaks Shivdasani Foundation
- Merck Research Laboratories
- High Performance Computing group at Merck Co., Inc.
- EPSRC [EP/I034602/1, EP/L00030X/1, EP/I017909/1] Funding Source: UKRI
- MRC [MR/L016311/1] Funding Source: UKRI
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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.
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