Crystal structures of diverse protein kinase catalytic subunits reveal a number of water molecules whose positions within the protein core are better preserved than amino acid types in many functionally important locations. It remains unknown whether they play any particular role, and whether their removal, disturbing local interaction patterns to no smaller degree than amino acid mutations, can affect kinase stability and function. In this study, we apply an array of computational approaches to characterize hydration of kinase catalytic subunits. First, we systematically screen multiple crystal structures with the use of a simplified hydration model in order to determine the distribution of internal solvent and the degree of its conservation. Second, we analyze water structure, dynamics and binding affinity to buried hydration sites in a number of kinases, also taking into account their variable functional state. We find that a large portion of buried solvent is dynamic, possibly contributing to kinase conformational changes related to the activation process. In turn, binding free energies of some of tightly bound conserved water molecules to different kinases tend to shift in a similar manner following the change of their functional state. This finding highlights the likely specific role of internal solvent in fine tuning local protein plasticity.

中文翻译：

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蛋白质激酶中保守的内部水合基序。

多种蛋白激酶催化亚基的晶体结构揭示了许多水分子，这些蛋白分子在蛋白质核心中的位置比许多功能上重要的位置的氨基酸类型保留得更好。仍然不清楚它们是否发挥任何特殊作用，以及它们的去除是否会干扰氨基酸相互作用的程度不小于氨基酸突变，从而影响激酶的稳定性和功能。在这项研究中，我们应用了一系列计算方法来表征激酶催化亚基的水合作用。首先，我们使用简化的水合模型系统地筛选多个晶体结构，以确定内部溶剂的分布及其保守程度。其次，我们分析水的结构 动力学和对许多激酶中隐蔽水合位点的结合亲和力，还考虑了它们可变的功能状态。我们发现大部分埋藏的溶剂是动态的，可能导致与激活过程有关的激酶构象变化。继而，一些紧密结合的保守水分子与不同激酶的结合自由能倾向于以相似的方式随着其功能状态的改变而移动。这一发现突显了内部溶剂在微调局部蛋白质可塑性中可能发挥的特定作用。一些紧密结合的保守水分子与不同激酶的结合自由能往往会随着其功能状态的改变而以类似的方式移动。这一发现突显了内部溶剂在微调局部蛋白质可塑性中可能发挥的特定作用。一些紧密结合的保守水分子与不同激酶的结合自由能往往会随着其功能状态的改变而以类似的方式移动。这一发现突显了内部溶剂在微调局部蛋白质可塑性中可能发挥的特定作用。