Oversampling Free Energy Perturbation Simulation in Determination of the Ligand-Binding Free Energy |
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Authors: | Son Tung Ngo Trung Hai Nguyen Nguyen Thanh Tung Pham Cam Nam Khanh B Vu Van V Vu |
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Institution: | 1. Laboratory of Theoretical and Computational Biophysics, Ton Duc Thang University, Ho Chi Minh City, Vietnam;2. Institute of Materials Science & Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Hanoi, Vietnam;3. Department of Chemical Engineering, The University of Da Nang, University of Science and Technology, Da Nang City, Vietnam;4. NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam |
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Abstract: | 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 ( RREP = 0.85 ± 0.15 ) is significantly boosted in comparison with the FEP one ( RFEP = 0.64 ± 0.30 ). Furthermore, the root-mean-square error (RMSE) of REP is also smaller than FEP, RMSEREP = 4.28 ± 0.69 versus RMSEFEP = 5.80 ± 1.11 kcal/mol, respectively. © 2019 Wiley Periodicals, Inc. |
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Keywords: | perturbation replica exchange molecular dynamics REP FEP binding free energy |
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