Accuracy and Precision of Alchemical Relative Free Energy Predictions with and without Replica-Exchange.

ABSTRACT: 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.

SUBMITTER: Wan S 

PROVIDER: S-EPMC8427472 | biostudies-literature |

REPOSITORIES: biostudies-literature