Oversampling Free Energy Perturbation Simulation in Determination of the Ligand‐Binding Free Energy,Journal of Computational Chemistry

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Oversampling Free Energy Perturbation Simulation in Determination of the Ligand‐Binding Free Energy
Journal of Computational Chemistry ( IF 3.4 ) Pub Date : 2019-12-16 , DOI: 10.1002/jcc.26130
Son Tung Ngo _{1,

2} , Trung Hai Nguyen _{1,

2} , Nguyen Thanh Tung ₃ , Pham Cam Nam ₄ , Khanh B Vu ₅ , Van V Vu ₅

Affiliation

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.

中文翻译：

确定配体结合自由能的过采样自由能扰动模拟

确定配体结合亲和力是一个非常有趣的问题。通常，自由能扰动 (FEP) 方法可提供适当的结果。然而，提高该方法的准确度和精密度具有重要意义。在这种情况下，提出了 FEP 计算方法的温度副本交换分子动力学实现，我们称之为副本交换自由能扰动 (REP)。特别是，在 REP 模拟过程中，系统可以通过与高温交换配置轻松摆脱陷入局部最小值的困境，从而显着提高蛋白质-配体结合亲和力计算的准确性和精确度。解耦自由能分布扩大，均值降低。这导致计算出的结合自由能的大小发生变化以及结合机制的改变。此外，与 FEP (RFEP = 0.64 ± 0.30) 相比，与实验相关的 REP 相关系数 (RREP = 0.85 ± 0.15) 显着提高。此外，REP 的均方根误差 (RMSE) 也小于 FEP，分别为 RMSEREP = 4.28 ± 0.69 与 RMSEFEP = 5.80 ± 1.11 kcal/mol。© 2019 威利期刊公司。69 与 RMSEFEP = 5.80 ± 1.11 kcal/mol，分别。© 2019 威利期刊公司。69 与 RMSEFEP = 5.80 ± 1.11 kcal/mol，分别。© 2019 威利期刊公司。

更新日期：2019-12-16

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