The value of thoroughly understanding the thermodynamics specific to a drug discovery/design study is well known. Over the past decade, the crucial roles of water molecules in protein structure, function, and dynamics have also become increasingly appreciated. This Perspective explores water in the biological environment by adopting its point of view in such phenomena. The prevailing thermodynamic models of the past, where water was seen largely in terms of an entropic gain after its displacement by a ligand, are now known to be much too simplistic. We adopt a set of terminology that describes water molecules as being “hot” and “cold”, which we have defined as being easy and difficult to displace, respectively. The basis of these designations, which involve both enthalpic and entropic water contributions, are explored in several classes of biomolecules and structural motifs. The hallmarks for characterizing water molecules are examined, and computational tools for evaluating water-centric thermodynamics are reviewed. This Perspective’s summary features guidelines for exploiting water molecules in drug discovery.

中文翻译：

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水在蛋白质基质中的作用：药物开发中尚未开发的资源

全面了解特定于药物发现/设计研究的热力学的价值是众所周知的。在过去的十年中，水分子在蛋白质结构，功能和动力学中的关键作用也日益受到人们的重视。本透视图通过采用这种现象的观点来探索生物环境中的水。过去流行的热力学模型非常简单化，在该模型中，水在很大程度上被配体取代后的熵增加。我们采用一组术语将水分子描述为“热”和“冷”，我们将其分别定义为易于置换和难以置换。这些名称的基础涉及焓水和熵水，在几类生物分子和结构基序中进行了探索。审查了表征水分子的标志，并审查了用于评估以水为中心的热力学的计算工具。该观点的摘要提供了在药物开发中利用水分子的指导原则。