Predicting Displaceable Water Sites Using Mixed-Solvent Molecular Dynamics,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Predicting Displaceable Water Sites Using Mixed-Solvent Molecular Dynamics
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2018-01-16 00:00:00 , DOI: 10.1021/acs.jcim.7b00268
Sarah E Graham ₁ , Richard D Smith ₁ , Heather A Carlson ₁

Affiliation

Water molecules are an important factor in protein–ligand binding. Upon binding of a ligand with a protein’s surface, waters can either be displaced by the ligand or may be conserved and possibly bridge interactions between the protein and ligand. Depending on the specific interactions made by the ligand, displacing waters can yield a gain in binding affinity. The extent to which binding affinity may increase is difficult to predict, as the favorable displacement of a water molecule is dependent on the site-specific interactions made by the water and the potential ligand. Several methods have been developed to predict the location of water sites on a protein’s surface, but the majority of methods are not able to take into account both protein dynamics and the interactions made by specific functional groups. Mixed-solvent molecular dynamics (MixMD) is a cosolvent simulation technique that explicitly accounts for the interaction of both water and small molecule probes with a protein’s surface, allowing for their direct competition. This method has previously been shown to identify both active and allosteric sites on a protein’s surface. Using a test set of eight systems, we have developed a method using MixMD to identify conserved and displaceable water sites. Conserved sites can be determined by an occupancy-based metric to identify sites which are consistently occupied by water even in the presence of probe molecules. Conversely, displaceable water sites can be found by considering the sites which preferentially bind probe molecules. Furthermore, the inclusion of six probe types allows the MixMD method to predict which functional groups are capable of displacing which water sites. The MixMD method consistently identifies sites which are likely to be nondisplaceable and predicts the favorable displacement of water sites that are known to be displaced upon ligand binding.

中文翻译：

使用混合溶剂分子动力学预测可置换水位点

水分子是蛋白质-配体结合的重要因素。当配体与蛋白质表面结合时，水可以被配体取代，或者可以被保留并可能桥接蛋白质和配体之间的相互作用。根据配体产生的特定相互作用，置换水可以提高结合亲和力。结合亲和力可能增加的程度很难预测，因为水分子的有利位移取决于水和潜在配体产生的位点特异性相互作用。已经开发了几种方法来预测蛋白质表面上水位点的位置，但大多数方法无法同时考虑蛋白质动力学和特定官能团产生的相互作用。混合溶剂分子动力学 (MixMD) 是一种共溶剂模拟技术，可明确解释水和小分子探针与蛋白质表面的相互作用，从而允许它们直接竞争。该方法之前已被证明可以识别蛋白质表面的活性位点和变构位点。通过使用由八个系统组成的测试集，我们开发了一种使用 MixMD 来识别保护水源和可替代水源的方法。可以通过基于占用的度量来确定保守位点，以识别即使在存在探针分子的情况下也始终被水占据的位点。相反，可通过考虑优先结合探针分子的位点来找到可置换的水位点。此外，包含六种探针类型使得 MixMD 方法能够预测哪些官能团能够取代哪些水位点。 MixMD 方法始终如一地识别可能不可置换的位点，并预测已知在配体结合时被置换的水位点的有利置换。

更新日期：2018-01-16

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11