Sampling protein motion and solvent effect during ligand binding
Sampling protein motion and solvent effect during ligand binding
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DOI：
10.1073/pnas.1112181108
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发表时间：
2012-01-31
影响因子：
11.1
通讯作者：
Parrinello, Michele
中科院分区：
文献类型：
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作者：
Limongelli, Vittorio;Marinelli, Luciana;Parrinello, Michele
配体与其生物靶标之间的分子识别机制的详尽描述具有重要价值，因为它为相关过程的外源控制提供了机会。通常，可以使用复合物的高分辨率结构结合廉价的计算协议（例如对接算法）来追求该目标。不幸的是，在许多其他情况下，许多因素，如蛋白质的灵活性或溶剂效应，增加了配体/蛋白质相互作用的复杂程度，这些标准技术不再足以描述结合事件。在本研究中，我们已经经历并测试了这些限制，我们已经开发并揭示了一系列新的腺苷脱氨酶强效抑制剂的结合机制。我们首先进行了大量的对接计算，不幸的是，由于酶的动力学特性和溶剂的复杂作用，未能产生可靠的结果。因此，我们已经加强了计算策略，使用基于元自组织的协议。我们的方法允许处理蛋白质运动和溶剂化过程中的配体结合，并最终确定最有效的化合物的系列，4-癸基-吡唑并[1，5-a]嘧啶-7-酮的最低能量结合模式。
An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5-a]pyrimidin-7-one.