Journal
ADVANCED THEORY AND SIMULATIONS
Volume 3, Issue 1, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adts.201900195
Keywords
binding free energies; FEP+; replica-exchange; thermodynamic integration with enhanced sampling
Categories
Funding
- UK Medical Research Council [MR/L016311/1]
- Qatar National Research Fund [7-1083-1-191]
- NSF [NSF 1713749]
- UCL Provost
- Office of Science of the U.S. Department of Energy [DE-AC05-00OR22725]
- EU H2020 project ComPat [671564]
- EU H2020 project CompBioMed
- EU H2020 project CompBioMed2 [675451, 823712]
- MRC [MR/L016311/1] Funding Source: UKRI
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A systematic and statistically robust protocol is applied for the evaluation of free energy calculations with and without replica-exchange. The protocol is based on ensemble averaging to generate accurate assessments of the uncertainties in the predictions. Comparison is made between FEP+ and TIES-free energy perturbation and thermodynamic integration with enhanced sampling-the latter with and without the so-called enhanced sampling based on replica-exchange protocols. Standard TIES performs best for a reference set of targets and compounds; no benefits accrue from replica-exchange methods. Evaluation of FEP+ and TIES with REST-replica-exchange with solute tempering-reveals a systematic and significant underestimation of free energy differences in FEP+, which becomes increasingly large for long duration simulations, is confirmed by extensive analysis of previous publications, and raises a number of questions pertaining to the accuracy of the predictions with the REST technique not hitherto discussed.
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