Side-chain rotamer changes upon ligand binding: common, crucial, correlate with entropy and rearrange hydrogen bonding.
Side-chain rotamer changes upon ligand binding: common, crucial, correlate with entropy and rearrange hydrogen bonding.
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DOI：
10.1093/bioinformatics/bts395
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发表时间：
2012-09-15
期刊：
影响因子：
--
通讯作者：
Najmanovich R
中科院分区：
文献类型：
--
作者：
Gaudreault F;Chartier M;Najmanovich R
动机：蛋白质运动形成从大结构域重排（包括折叠和重组）到侧链旋转异构体变化和小重排的连续体。了解结合时的侧链柔性对于了解分子识别事件和预测配体结合是重要的。研究方法：在目前的工作中，我们开发了一个精心策划的非冗余数据集，其中包含188种蛋白质，以Apo（未结合）和Holo（结合）形式成对的结构，以研究结合后指导侧链旋转异构体变化的程度和因素。结果：我们的分析表明，侧链旋转异构体的变化很普遍，只有10%的结合位点没有显示出构象变化。总体而言，在90%的情况下，最多五个旋转异构体的变化可以解释观察到的运动。此外，旋转异构体的变化是必不可少的32%的灵活的结合位点。不同的氨基酸发生变化的概率有11倍的差异。侧链柔性代表氨基酸的固有性质，因为它与构型熵差异密切相关。此外，平均b因子和溶剂可及表面积可以区分载脂蛋白形式的柔性侧链。最后，在结合时，氢键网络发生重排，主要是失去与水分子的氢键，并获得与蛋白质残基的氢键。有趣的是，只有25%的侧链能够在结合时与配体形成氢键。在药物设计方面，这最后一个结果表明，有大量的潜在的相互作用，可用于调节抑制剂的特异性和敏感性。联系人：rafael. usherbrooke.ca
Motivation: Protein movements form a continuum from large domain rearrangements (including folding and restructuring) to side-chain rotamer changes and small rearrangements. Understanding side-chain flexibility upon binding is important to understand molecular recognition events and predict ligand binding. Methods: In the present work, we developed a well-curated non-redundant dataset of 188 proteins in pairs of structures in the Apo (unbound) and Holo (bound) forms to study the extent and the factors that guide side-chain rotamer changes upon binding. Results: Our analysis shows that side-chain rotamer changes are widespread with only 10% of binding sites displaying no conformational changes. Overall, at most five rotamer changes account for the observed movements in 90% of the cases. Furthermore, rotamer changes are essential in 32% of flexible binding sites. The different amino acids have a 11-fold difference in their probability to undergo changes. Side-chain flexibility represents an intrinsic property of amino acids as it correlates well with configurational entropy differences. Furthermore, on average b-factors and solvent accessible surface areas can discriminate flexible side-chains in the Apo form. Finally, there is a rearrangement of the hydrogen-bonding network upon binding primarily with a loss of H-bonds with water molecules and a gain of H-bonds with protein residues for flexible residues. Interestingly, only 25% of side chains capable of forming H-bonds do so with the ligand upon binding. In terms of drug design, this last result shows that there is a large number of potential interactions that may be exploited to modulate the specificity and sensitivity of inhibitors. Contact: rafael.najmanovich@usherbrooke.ca
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