Open AccessProtein Loop Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates
Author(s) -
Shima Arasteh,
Bin W. Zhang,
Ronald M. Levy
Publication year - 2021
Publication title -
the journal of physical chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.563
H-Index - 203
ISSN - 1948-7185
DOI - 10.1021/acs.jpclett.1c00778
Subject(s) - metadynamics , free energy perturbation , umbrella sampling , conformational change , chemistry , perturbation (astronomy) , energy (signal processing) , crystallography , computational chemistry , physics , molecular dynamics , stereochemistry , quantum mechanics
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.