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.
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| http://dx.doi.org/10.1021/acs.jpclett.1c00778 | DOI Listing |
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