The Thermodynamics of Protein-Ligand Interaction and Solvation: Insights for Ligand Design
The Thermodynamics of Protein-Ligand Interaction and Solvation: Insights for Ligand Design
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DOI：
10.1016/j.jmb.2008.09.073
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发表时间：
2008-12-26
影响因子：
5.6
通讯作者：
Ladbury, John E.
中科院分区：
文献类型：
--
作者：
Olsson, Tjelvar S. G.;Williams, Mark A.;Ladbury, John E.
等温滴定量热法能够提供关于焓和熵变化对结合自由能的热力学贡献的准确信息。已发表的等温滴定量热法研究和蛋白质与小分子配体之间相互作用的结构信息的结构/量热法报告蛋白质相互作用在线数据库在这里用于揭示蛋白质-配体相互作用的一般热力学性质，并研究与溶剂化变化的相关性。绝大多数的相互作用被发现是有利的。合成抑制剂和生物配体在数据中形成了两个不同的亚群，由于结合时的熵变化更有利，前者具有更大的平均亲和力。最大的相关性被发现之间的结合自由能和非极性表面埋后，复杂的形成。然而，每单位面积掩埋的自由能贡献仅为早期小分子转移自由能研究所预期的30-50%。一个简单的概率为基础的估计结合位点的最大亲和力在其非极性表面积的建议。极表面积埋藏也对亲和力有很大的贡献，但由于极表面积埋藏量的变化很小，并且有抵消其热力学和熵贡献的趋势，因此很难用单位面积来表示。传统上，非极性去溶剂化对亲和力的贡献归因于溶剂释放引起的熵增益。虽然这里提供的数据支持这一观点，因为熵变与非极性表面埋藏的相关性相对较弱，但根据目前的证据，它不能被确信地认为是正确的。此外，热力学变化所产生的配体之间的小差异结合到个别蛋白质是相对较大的，一般来说，与溶剂化的变化不相关，这表明在广泛不同的蛋白质中确定的趋势是有限的使用在解释或预测配体修饰的影响。(C)2008爱思唯尔有限公司保留所有权利。
Isothermal titration calorimetry is able to provide accurate information on the thermodynamic contributions of enthalpy and entropy changes to free energies of binding. The Structure/Calorimetry of Reported Protein Interactions Online database of published isothermal titration calorimetry studies and structural information on the interactions between proteins and small-molecule ligands is used here to reveal general thermodynamic properties of protein-ligand interactions and to investigate correlations with changes in solvation. The overwhelming majority of interactions are found to be enthalpically favoured. Synthetic inhibitors and biological ligands form two distinct subpopulations in the data, with the former having greater average affinity due to more favourable entropy changes on binding. The greatest correlation is found between the binding free energy and apolar surface burial upon complex formation. However, the free-energy contribution per unit area buried is only 30-50% of that expected from earlier studies of transfer free energies of small molecules. A simple probability-based estimator for the maximal affinity of a binding site in terms of its apolar surface area is proposed. Polar surface area burial also contributes substantially to affinity but is difficult to express in terms of unit area due to the small variation in the amount of polar surface buried and a tendency for cancellation of its enthalpic and entropic contributions. Conventionally, the contribution of apolar desolvation to affinity is attributed to gain of entropy due to solvent release. Although data presented here are supportive of this notion, because the correlation of entropy change with apolar surface burial is relatively weak, it cannot, on present evidence, be confidently considered to be correct. Further, thermodynamic changes arising from small differences between ligands binding to individual proteins are relatively large and, in general, uncorrelated with changes in solvation, suggesting that trends identified across widely differing proteins are of limited use in explaining or predicting the effects of ligand modifications. (C) 2008 Elsevier Ltd. All rights reserved.