Institute for Computational Science and Technology, Thu Duc District, Ho Chi Minh City, Vietnam.
J Chem Inf Model. 2011 Sep 26;51(9):2266-76. doi: 10.1021/ci2000743. Epub 2011 Aug 23.
An accurate estimation of binding free energy of a ligand to receptor ΔG(bind) is one of the most important problems in drug design. The success of solution of this problem is expected to depend on force fields used for modeling a ligand-receptor complex. In this paper, we consider the impact of four main force fields, AMBER99SB, CHARMM27, GROMOS96 43a1, and OPLS-AA/L, on the binding affinity of Oseltamivir carboxylate to the wild-type and Y252H, N294S, and H274Y mutants of glycoprotein neuraminidase from the pandemic A/H5N1 virus. Having used the molecular mechanic-Poisson-Boltzmann surface area method, we have shown that ΔG(bind), obtained by AMBER99SB, OPLS-AA/L, and CHARMM27, shows the high correlation with the available experimental data. They correctly capture the binding ranking Y252H → WT → N294S → H274Y observed in experiments (Collins, P. J. et al. Nature 2008, 453, 1258). In terms of absolute values of binding scores, results obtained by AMBER99SB are in the nearest range with experiments, while OPLS-AA/L, which is applied to study binding of Oseltamivir to the influenza virus for the first time, gives rather big negative values for ΔG(bind). GROMOS96 43a1 provides a lower correlation as it supports Oseltamivir to be more resistant to N294S than H274Y. Our study suggests that force fields have pronounced influence on theoretical estimations of binding free energy of a ligand to receptor. The effect of all-atom models on dynamics of the binding pocket as well as on the hydrogen-bond network between Oseltamivir and receptors is studied in detail. The hydrogen network, obtained by GROMOS, is weakest among four studied force fields.
配体与受体结合自由能 ΔG(bind) 的准确估计是药物设计中最重要的问题之一。预计解决这个问题的成功将取决于用于模拟配体-受体复合物的力场。在本文中，我们考虑了四种主要力场，即 AMBER99SB、CHARMM27、GROMOS96 43a1 和 OPLS-AA/L，对奥司他韦羧酸盐与野生型和 Y252H、N294S 和 H274Y 突变的糖蛋白神经氨酸酶的结合亲和力的影响来自大流行性 A/H5N1 病毒。使用分子力学-泊松-玻尔兹曼表面面积方法，我们表明，由 AMBER99SB、OPLS-AA/L 和 CHARMM27 获得的 ΔG(bind) 与可用的实验数据具有高度相关性。它们正确地捕捉到了实验中观察到的结合排序 Y252H → WT → N294S → H274Y（Collins，PJ 等人，自然 2008，453，1258）。就结合评分的绝对值而言，AMBER99SB 获得的结果与实验最为接近，而 OPLS-AA/L 首次应用于研究奥司他韦与流感病毒的结合，给出了相当大的负值 ΔG(bind)。GROMOS96 43a1 提供的相关性较低，因为它支持奥司他韦对 N294S 的耐药性高于 H274Y。我们的研究表明，力场对配体与受体结合自由能的理论估计有显著影响。详细研究了全原子模型对结合口袋动力学以及奥司他韦与受体之间氢键网络的影响。在所研究的四个力场中，GROMOS 获得的氢键网络最弱。
