Explicit Treatment of Water Molecules in Data-Driven Protein-Protein Docking: The Solvated HADDOCKing Approach
Explicit Treatment of Water Molecules in Data-Driven Protein-Protein Docking: The Solvated HADDOCKing Approach
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DOI：
10.1007/978-1-61779-465-0_22
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Bonvin, Alexandre M. J. J.
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文献类型：
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作者：
Kastritis, Panagiotis L.;van Dijk, Aalt D. J.;Bonvin, Alexandre M. J. J.
水分子实际上是每个生化事件中的活性成分，形成氢键、填充空腔并介导与其他（生物）分子的相互作用。因此，溶剂极大地影响许多细胞事件的动力学和热力学，包括蛋白质相互作用。虽然对接技术在预测蛋白质复合物的三维结构方面取得了成功，但它们在明确解释结合过程中的水方面仍然受到限制。 HADDOCK 是迄今为止为数不多的能够在对接过程中明确处理水分子的程序之一。其溶剂化对接方案从水合分子开始，随后通过偏向蒙特卡罗程序从对接模型中去除一部分界面水。基于蒙特卡罗的去除基于源自蛋白质复合物高分辨率晶体结构数据集的界面氨基酸水接触倾向。在本章中，描述了这种溶剂化对接协议，并通过应用示例说明了相关的方法学方面。结果表明，虽然应用溶剂化对接方案时对接结果并不总是得到改善，但评分得到改善并且界面中埋藏水分子的位置得到了正确预测。因此，通过识别重要的水分子，溶剂化对接可以帮助开发可能更好地适应界面的新型蛋白质复合物抑制剂。
Water molecules are active components in, literally, every biochemical event, forming hydrogen bonds, filling cavities, and mediating interactions with other (bio)molecules. Therefore, solvent drastically affects the kinetics and thermodynamics of numerous cellular events, including protein protein interactions. While docking techniques arc becoming successful in predicting the three-dimensional structure of protein protein complexes, they are still limited in accounting explicitly for water in the binding process. HADDOCK is one of the few programs so far that can explicitly deal with water molecules during docking. Its solvated docking protocol starts from hydrated molecules, and a fraction of the interfacial water is subsequently removed from the docked models in a biased Monte Carlo procedure. The Monte Carlo-based removal is based on interfacial amino acid water contact propensities derived from a dataset of high-resolution crystal structures of protein protein complexes. In this chapter, this solvated docking protocol is described and associated methodological aspects arc illustrated through an application example. It is shown that, although docking results do not always improve when the solvated docking protocol is applied, scoring is improved and the positions of buried water molecules in an interface are correctly predicted. Therefore, by identifying important water molecules, solvated docking can aid the development of novel inhibitors of protein protein complexes that might be better accommodated at an interface.