Tsai C J, Lin S L, Wolfson H J, Nussinov R
Laboratory of Mathematical Biology, NCI-FCRF, Frederick, Maryland 21702, USA.
Protein Sci. 1997 Jan;6(1):53-64. doi: 10.1002/pro.5560060106.
Data sets of 362 structurally nonredundant protein-protein interfaces and of 57 symmetry-related oligomeric interfaces have been used to explore whether the hydrophobic effect that guides protein folding is also the main driving force for protein-protein associations. The buried nonpolar surface area has been used to measure the hydrophobic effect. Our analysis indicates that, although the hydrophobic effect plays a dominant role in protein-protein binding, it is not as strong as that observed in the interior of protein monomers. Comparison of interiors of the monomers with those of the interfaces reveals that, in general, the hydrophobic amino acids are more frequent in the interior of the monomers than in the interior of the protein-protein interfaces. On the other hand, a higher proportion of charged and polar residues are buried at the interfaces, suggesting that hydrogen bonds and ion pairs contribute more to the stability of protein binding than to that of protein folding. Moreover, comparison of the interior of the interfaces to protein surfaces indicates that the interfaces are poorer in polar/charged than the surfaces and are richer in hydrophobic residues. The interior of the interfaces appears to constitute a compromise between the stabilization contributed by the hydrophobic effect on the one hand and avoiding patches on the protein surfaces that are too hydrophobic on the other. Such patches would be unfavorable for the unassociated monomers in solution. We conclude that, although the types of interactions are similar between protein-protein interfaces and single-chain proteins overall, the contribution of the hydrophobic effect to protein-protein associations is not as strong as to protein folding. This implies that packing patterns and interatom, or interresidue, pairwise potential functions, derived from monomers, are not ideally suited to predicting and assessing ligand associations or design. These would perform adequately only in cases where the hydrophobic effect at the binding site is substantial.
362个结构上非冗余的蛋白质-蛋白质界面数据集和57个对称相关的寡聚体界面数据集已被用于探究引导蛋白质折叠的疏水效应是否也是蛋白质-蛋白质缔合的主要驱动力。埋藏的非极性表面积已被用于衡量疏水效应。我们的分析表明，尽管疏水效应在蛋白质-蛋白质结合中起主导作用，但它不如在蛋白质单体内部观察到的那么强。单体内部与界面内部的比较表明，一般来说，疏水氨基酸在单体内部比在蛋白质-蛋白质界面内部更常见。另一方面，更高比例的带电荷和极性残基埋藏在界面处，这表明氢键和离子对在蛋白质结合稳定性上的贡献比在蛋白质折叠稳定性上的贡献更大。此外，界面内部与蛋白质表面的比较表明，界面处的极性/带电荷残基比表面少，疏水残基比表面多。界面内部似乎构成了一方面由疏水效应贡献的稳定性与另一方面避免蛋白质表面过于疏水的区域之间的一种折衷。这样的区域对于溶液中未缔合的单体是不利的。我们得出结论，尽管蛋白质-蛋白质界面和单链蛋白质之间总体上相互作用的类型相似，但疏水效应在蛋白质-蛋白质缔合中的贡献不如在蛋白质折叠中的贡献那么强。这意味着从单体衍生而来的堆积模式和原子间或残基间的成对势函数并不理想地适合于预测和评估配体缔合或设计。这些仅在结合位点的疏水效应显著的情况下才会表现良好。
