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Arasteh S , Zhang BW , Levy RM
Protein Loop Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates
J Phys Chem Lett. 2021 May 13;12(18) :4368-4377
PMID: 33938761    PMCID: PMC8170697    URL: https://www.ncbi.nlm.nih.gov/pubmed/33938761
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Abstract
We introduce a method called restrain-free energy perturbation-release 2.0 (R-FEP-R 2.0) to estimate conformational free energy changes of protein loops via an alchemical path. R-FEP-R 2.0 is a generalization of the method called restrain-free energy perturbation-release (R-FEP-R) that can only estimate conformational free energy changes of protein side chains but not loops. The reorganization of protein loops is a central feature of many biological processes. Unlike other advanced sampling algorithms such as umbrella sampling and metadynamics, R-FEP-R and R-FEP-R 2.0 do not require predetermined collective coordinates and transition pathways that connect the two endpoint conformational states. The R-FEP-R 2.0 method was applied to estimate the conformational free energy change of a β-turn flip in the protein ubiquitin. The result obtained by R-FEP-R 2.0 agrees with the benchmarks very well. We also comment on problems commonly encountered when applying umbrella sampling to calculate protein conformational free energy changes.
Notes
1948-7185 Arasteh, Shima Orcid: 0000-0002-9723-0317 Zhang, Bin W Orcid: 0000-0003-3007-4900 Levy, Ronald M Orcid: 0000-0001-8696-5177 Journal Article United States J Phys Chem Lett. 2021 May 13;12(18):4368-4377. doi: 10.1021/acs.jpclett.1c00778. Epub 2021 May 3.