Hybrid Molecular Dynamics for Elucidating Cooperativity Between Halogen Bond and Water Molecules During the Interaction of p53-Y220C and the PhiKan5196 Complex
Hybrid Molecular Dynamics for Elucidating Cooperativity Between Halogen Bond and Water Molecules During the Interaction of p53-Y220C and the PhiKan5196 Complex
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杂化分子动力学用于阐明 p53-Y220C 与 PhiKan5196 复合物相互作用过程中卤素键与水分子之间的协同作用
DOI：
10.3389/fchem.2020.00344
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发表时间：
2020-05-07
影响因子：
5.5
通讯作者：
Gao，Jun
中科院分区：
文献类型：
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作者：
Dong，Tian-ge;Peng，Hui;Gao，Jun
氢键和卤键之间的协同作用在药物设计中起着重要的作用。然而，模拟这些键之间的动态合作是一个具有挑战性的问题，这阻碍了卤素键力场的发展。以p53蛋白Y220 C-PhiKan 5196复合物为模型，采用量子力学/分子力学混合动力学方法模拟分析了与卤素原子形成氢键的3个水分子的作用.与无水模型的比较表明，复合物中卤键的强度始终更强。这证实了水分子与卤素原子形成弱氢键，并与卤素原子合作以增强卤素键。此外，还发现这三种水分子的作用并不相同。因此，本文获得的结果可以促进合理的药物设计。此外，这项工作强调的事实是，除了蛋白质口袋和配体，空隙的作用也应该考虑到它们周围的水分子。
The cooperativity between hydrogen and halogen bonds plays an important role in rational drug design. However, mimicking the dynamic cooperation between these bonds is a challenging issue, which has impeded the development of the halogen bond force field. In this study, the Y220C–PhiKan5196 complex of p53 protein was adopted as a model, and the functions of three water molecules that formed hydrogen bonds with halogen atoms were analyzed by the simulation method governed by the hybrid quantum mechanical/molecular mechanical molecular dynamics. A comparison with the water-free model revealed that the strength of the halogen bond in the complex was consistently stronger. This confirmed that the water molecules formed weak hydrogen bonds with the halogen atom and cooperated with the halogen atom to enhance the halogen bond. Further, it was discovered that the roles of the three water molecules were not the same. Therefore, the results obtained herein can facilitate a rational drug design. Further, this work emphasizes on the fact that, in addition to protein pockets and ligands, the role of voids should also be considered with regard to the water molecules surrounding them.