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Oversampling Free Energy Perturbation Simulation in Determination of the Ligand‐Binding Free Energy
Author(s) -
Ngo Son Tung,
Nguyen Trung Hai,
Tung Nguyen Thanh,
Nam Pham Cam,
Vu Khanh B.,
Vu Van V.
Publication year - 2020
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.26130
Subject(s) - free energy perturbation , decoupling (probability) , chemistry , perturbation (astronomy) , maxima and minima , molecular dynamics , ligand (biochemistry) , replica , binding energy , computational chemistry , statistical physics , molecular physics , thermodynamics , physics , atomic physics , quantum mechanics , mathematics , mathematical analysis , art , biochemistry , receptor , control engineering , engineering , visual arts
Determination of the ligand‐binding affinity is an extremely interesting problem. Normally, the free energy perturbation (FEP) method provides an appropriate result. However, it is of great interest to improve the accuracy and precision of this method. In this context, temperature replica exchange molecular dynamics implementation of the FEP computational approach, which we call replica exchange free energy perturbation (REP) was proposed. In particular, during REP simulations, the system can easily escape from being trapped in local minima by exchanging configurations with high temperatures, resulting in significant improvement in the accuracy and precision of protein–ligand binding affinity calculations. The distribution of the decoupling free energy was enlarged, and its mean values were decreased. This results in changes in the magnitude of the calculated binding free energies as well as in alteration in the binding mechanism. Moreover, the REP correlation coefficient with respect to experiment ( R REP = 0.85 ± 0.15 ) is significantly boosted in comparison with the FEP one ( R FEP = 0.64 ± 0.30 ). Furthermore, the root‐mean‐square error (RMSE) of REP is also smaller than FEP, RMSE REP = 4.28 ± 0.69 versus RMSE FEP = 5.80 ± 1.11 kcal/mol, respectively. © 2019 Wiley Periodicals, Inc.