Dhulesia Anne, Gsponer Joerg, Vendruscolo Michele
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
J Am Chem Soc. 2008 Jul 16;130(28):8931-9. doi: 10.1021/ja0752080. Epub 2008 Jun 18.
We describe the changes in structure and dynamics that occur in the second PDZ domain of human tyrosine phosphatase 1E upon binding the small peptide RA-GEF2 by an analysis of NMR data based on their use as ensemble-averaged restraints in molecular dynamics simulations. This approach reveals the presence of two interconnected networks of residues, the first exhibiting structural changes and the second dynamical changes upon binding, and it provides a detailed mapping of the regions of increased and decreased mobility upon binding. Analysis of the dynamical properties of the residues in these networks reveals that conformational changes are transmitted through pathways of coupled side-chain reorientations. These results illustrate how the strategy we described, in which NMR data are used in combination with molecular dynamics simulations, can be used to characterize in detail the complex organization of the changes in structure and dynamics that take place in proteins upon binding.
我们通过在分子动力学模拟中使用NMR数据作为系综平均约束来分析，描述了人酪氨酸磷酸酶1E的第二个PDZ结构域在结合小肽RA-GEF2时发生的结构和动力学变化。这种方法揭示了两个相互连接的残基网络的存在，第一个在结合时表现出结构变化，第二个表现出动力学变化，并且它提供了结合时流动性增加和减少区域的详细图谱。对这些网络中残基动力学性质的分析表明，构象变化是通过耦合侧链重新定向的途径传递的。这些结果说明了我们所描述的策略，即NMR数据与分子动力学模拟相结合，如何能够详细表征蛋白质在结合时发生的结构和动力学变化的复杂组织。
