Department of Biochemistry, Université de Sherbrooke, 3001, Québec, Canada J1H 5N4.
Bioinformatics. 2012 Sep 15;28(18):i423-i430. doi: 10.1093/bioinformatics/bts395.
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.
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.
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.
蛋白质的运动形成一个连续统，从大的结构域重排（包括折叠和重构）到侧链构象变化和小的重排。理解结合时侧链的灵活性对于理解分子识别事件和预测配体结合至关重要。
在本工作中，我们开发了一个精心挑选的非冗余数据集，其中包含 188 对apo（未结合）和holo（结合）形式的蛋白质结构，以研究结合时侧链构象变化的程度和指导因素。
我们的分析表明，侧链构象变化非常普遍，只有 10%的结合位点没有构象变化。总体而言，在 90%的情况下，最多有五个构象变化解释了观察到的运动。此外，在 32%的柔性结合位点中，构象变化是必不可少的。不同的氨基酸在发生变化的概率上有 11 倍的差异。侧链的灵活性是氨基酸的固有性质，因为它与构象熵的差异很好地相关。此外，平均 b 因子和溶剂可及表面积可以区分 apo 形式中柔性的侧链。最后，结合时氢键网络发生重排，主要是与水分子的氢键减少，与蛋白质残基的氢键增加，对于柔性残基。有趣的是，只有 25%的能够形成氢键的侧链在结合时与配体形成氢键。就药物设计而言，这最后一个结果表明，有大量潜在的相互作用可以被利用来调节抑制剂的特异性和敏感性。
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