This work describes the development and testing of a method for the identification and classification of conserved water molecules and their networks from molecular dynamics (MD) simulations. The conserved waters in the active sites of proteins influence protein–ligand binding. Recently, several groups have argued that a water network formed from conserved waters can be used to interpret the thermodynamic signature of the binding site. We implemented a novel methodology in which we apply the complex approach to categorize water molecules extracted from the MD simulation trajectories using clustering approaches. The main advantage of our methodology as compared to current state of the art approaches is the inclusion of the information on the orientation of hydrogen atoms to further inform the clustering algorithm and to classify the conserved waters into different subtypes depending on how strongly certain orientations are preferred. This information is vital for assessing the stability of water networks. The newly developed approach is described in detail as well as validated against known results from the scientific literature including comparisons with the experimental data on thermolysin, thrombin, and Haemophilus influenzae virulence protein SiaP as well as with the previous computational results on thermolysin. We observed excellent agreement with the literature and were also able to provide additional insights into the orientations of the conserved water molecules, highlighting the key interactions which stabilize them. The source code of our approach, as well as the utility tools used for visualization, are freely available on GitHub.

中文翻译：

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使用密度聚类方法对位置和方向数据进行药物设计的守恒水网络识别

这项工作描述了一种用于从分子动力学 (MD) 模拟中识别和分类守恒水分子及其网络的方法的开发和测试。蛋白质活性位点中的保守水影响蛋白质-配体结合。最近，几个小组认为，由保守水域形成的水网络可用于解释结合位点的热力学特征。我们实施了一种新的方法，在该方法中，我们应用复杂的方法对使用聚类方法从 MD 模拟轨迹中提取的水分子进行分类。与当前最先进的方法相比，我们的方法的主要优势在于包含了有关氢原子方向的信息，以进一步为聚类算法提供信息，并根据某些方向的偏好程度将保守水域分为不同的子类型. 该信息对于评估供水网络的稳定性至关重要。对新开发的方法进行了详细描述，并根据科学文献中的已知结果进行了验证，包括与嗜热菌蛋白酶、凝血酶和流感嗜血杆菌毒力蛋白 SiaP 以及之前对嗜热菌蛋白酶的计算结果。我们观察到与文献的高度一致，并且还能够提供对守恒水分子方向的更多见解，突出显示稳定它们的关键相互作用。我们方法的源代码以及用于可视化的实用工具可在 GitHub 上免费获得。