Molecular Simulations with Solvent Competition Quantify Water Displaceability and Provide Accurate Interaction Maps of Protein Binding Sites
Molecular Simulations with Solvent Competition Quantify Water Displaceability and Provide Accurate Interaction Maps of Protein Binding Sites
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DOI：
10.1021/jm5010418
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发表时间：
2014-10-23
影响因子：
7.3
通讯作者：
Barril, Xavier
中科院分区：
文献类型：
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作者：
Alvarez-Garcia, Daniel;Barril, Xavier
结合位点呈现出公认的配体必须满足的明确的相互作用模式。了解它们对于指导基于结构的药物发现项目至关重要。然而，复杂的方面，如蛋白质的灵活性或水溶剂化的影响，阻碍了准确的预测。对于极性接触尤其如此，极性接触受局部环境和离散水分子行为的影响很大。在这里，我们提出并验证MDmix（混合溶剂的分子动力学模拟）作为一种方法，它提供了比普通势（例如，GRID）。此外，MDmix还提供水置换性预测，比使用纯水作为溶剂的方法具有优势（例如，非均匀流体溶剂化理论）。使用当前的MD软件和硬件解决方案，可以在几个小时内获得预测，并以非常直观的方式可视化。因此，MDmix是日常基于结构的药物发现项目的理想补充。
Binding sites present well-defined interaction patterns that putative ligands must meet. Knowing them is essential to guide structure-based drug discovery projects. However, complex aspects of molecular recognition-such as protein flexibility or the effect of aqueous solvation-hinder accurate predictions. This is particularly true for polar contacts, which are heavily influenced by the local environment and the behavior of discrete water molecules. Here we present and validate MDmix (Molecular Dynamics simulations with mixed solvents) as a method that provides much more accurate interaction maps than ordinary potentials (e.g., GRID). Additionally, MDmix also affords water displaceability predictions, with advantages over methods that use pure water as solvent (e.g., inhomogeneous fluid solvation theory). With current MD software and hardware solutions, predictions can be obtained in a matter of hours and visualized in a very intuitive manner. Thus, MDmix is an ideal complement in everyday structure-based drug discovery projects.