Protein Loop Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates
journal contributionposted on 03.05.2021, 15:05 authored by Shima Arasteh, Bin W. Zhang, Ronald M. Levy
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.