Acidic groups docked to well defined wetted pockets at the core of the binding interface: a tale of scoring and missing protein interactions in CAPRI
Acidic groups docked to well defined wetted pockets at the core of the binding interface: a tale of scoring and missing protein interactions in CAPRI
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DOI：
10.1002/prot.21722
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发表时间：
2007-12-01
影响因子：
2.9
通讯作者：
Camacho, Carlos J.
中科院分区：
文献类型：
--
作者：
Bueno, Marta;Camacho, Carlos J.
卡普里（T24/25和T26）中的一些具有挑战性的目标涉及结合界面核心处的结合溶剂可接近的酸性残基，在那里它们总是被发现浸没在结晶沃茨。事实上，天冬氨酸和谷氨酸残基更有可能形成其周围结晶水分子的氢键网络的一部分，而不是形成一个埋藏的盐桥。有趣的是，许多介导酸性基团分子间相互作用的晶体沃茨已经存在于未结合结构中，这加强了一些水分子作为蛋白质结构延伸的概念。这与在结合界面周围发现的酸性基团形成普遍存在的盐桥形成对比，盐桥粘合高亲和力复合物，同时它们暴露于快速交换的水分子。正因为如此，二分法隐式溶剂评分函数未能通过优先考虑盐桥而不是水介导的接触来正确地对这些络合物进行排名。对目标24和目标26的详细分析揭示了晶体沃茨如何在结合之前形成酸性基团的结合腔，这与锚残基作为蛋白质识别介质的理论一致。
Some challenging targets in CAPRI (T24/25 and T26) involve binding solvent accessible acidic residues at the core of the binding interface, where they are always found immersed in crystal waters. In fact, Asp and Glu residues are more likely to form part of the hydrogen bond network of their surrounding crystal water molecules than to form a buried salt bridge. Interestingly, many of the crystal waters mediating the intermolecular interactions of the acidic groups are already present in the unbound structure, reinforcing the notion that some water molecules behave as an extension of the protein structure. This is in contrast to acidic groups found in the periphery of the binding interface that form ubiquitous salt bridges that cement the high affinity complex, while at the same time they are exposed to rapidly exchanging water molecules. Because of this, dichotomy implicit solvent scoring functions fail to properly rank these complexes by prioritizing salt bridges rather than water mediated contacts. A detailed analysis of Target 24, for which our group predicted two out of the four successful homology model complex structures, and Target26 reveal how crystal waters shape the binding cavities of acidic groups prior to binding, in agreement with the theory of anchor residues as mediators of protein recognition.