Dynamical view of the positions of key side chains in protein-protein recognition
Dynamical view of the positions of key side chains in protein-protein recognition
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DOI：
10.1016/s0006-3495(01)76044-4
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发表时间：
2001-02-01
影响因子：
3.4
通讯作者：
Camacho, CJ
中科院分区：
文献类型：
--
作者：
Kimura, SR;Brower, RC;Camacho, CJ
当一个受体及其配体的刚性结构被单独确定时，一些关键的侧链通常处于错误的位置。界面的这些扭曲导致亲和力的明显损失，并将不利地影响缔合动力学。通常认为相互作用的蛋白质应该驱动适当的构象变化，导致它们的互补性，但这一假说不能解释它们的快速结合率。然而，对Barstar、牛胰蛋白酶抑制剂和溶菌酶的独立结构中错误折叠的表面侧链进行纳秒显式溶剂分子动力学模拟表明，即使在任何受体-配体相互作用之前，关键侧链也经常访问复合体中的旋转构象。我们表明，这些简单的结构基序可以协调快速和高度特异的结合过程所需的大部分结合亲和力。对诱导配对的侧链也进行了鉴定。这些结果证实了溶剂-侧链相互作用在识别过程中起着关键作用。我们的发现也得到了结晶学数据的支持。
When a complex is constructed from the separately determined rigid structures of a receptor and its ligand, some key side chains are usually in wrong positions. These distortions of the interface yield an apparent loss in affinity and would unfavorably affect the kinetics of association. It is generally assumed that the interacting proteins should drive the appropriate conformational changes, leading to their complementarity, but this hypothesis does not explain their fast association rates. However, nanosecond explicit solvent molecular dynamics simulations of misfolded surface side chains from the independently solved structures of barstar, bovine pancreatic trypsin inhibitor, and lysozyme show that even before any receptor-ligand interaction, key side chains frequently visit the rotamer conformations seen in the complex. We show that these simple structural motifs can reconcile most of the binding affinity required for a rapid and highly specific association process. Side chains amenable to induced fit are also identified. These results corroborate that solvent-side chain interactions play a critical role in the recognition process. Our findings are also supported by crystallographic data.