Standard free energy of releasing a localized water molecule from the binding pockets of proteins: Double-decoupling method
Standard free energy of releasing a localized water molecule from the binding pockets of proteins: Double-decoupling method
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DOI：
10.1021/ja0377908
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发表时间：
2004-06-23
影响因子：
15
通讯作者：
McCammon, JA
中科院分区：
文献类型：
--
作者：
Hamelberg, D;McCammon, JA
蛋白质结合口袋中的局部水分子在蛋白质与小分子药物化合物的非共价缔合中起着重要作用。有时，结合自由能的主要贡献来自生物分子结合口袋中局部水分子的释放。因此，为了量化这些水分子在药物设计中的能量重要性，我们使用了双解耦方法来计算两个蛋白质复合物结合口袋中的水分子的标准自由能。双解耦方法基于统计热力学的基本原理。我们已经计算出的标准自由能捆绑在这些配合物的结合口袋中的水分子是有利的。这些水分子通过与配体和结合口袋相互作用来稳定蛋白质-药物复合物。我们的研究结果提供了可用于优化蛋白质-药物相互作用的想法，通过设计能够靶向蛋白质结合位点中的局部水分子的配体。配体结合的所得自由能可以受益于伴随这些水分子释放的潜在自由能增益。此外，我们还研究了双解耦方法的理论背景及其与分子动力学热力学积分技术的联系。
Localized water molecules in the binding pockets of proteins play an important role in noncovalent association of proteins and small drug compounds. At times, the dominant contribution to the binding free energy comes from the release of localized water molecules in the binding pockets of biomolecules. Therefore, to quantify the energetic importance of these water molecules for drug design purposes, we have used the double-decoupling approach to calculate the standard free energy of tying up a water molecule in the binding pockets of two protein complexes. The double-decoupling approach is based on the underlying principle of statistical thermodynamics. We have calculated the standard free energies of tying up the water molecule in the binding pockets of these complexes to be favorable. These water molecules stabilize the protein-drug complexes by interacting with the ligands and binding pockets. Our results offer ideas that could be used in optimizing protein-drug interactions, by designing ligands that are capable of targeting localized water molecules in protein binding sites. The resulting free energy of ligand binding could benefit from the potential free energy gain accompanying the release of these water molecules. Furthermore, we have examined the theoretical background of the double-decoupling method and its connection to the molecular dynamics thermodynamic integration techniques.