Sinha N, Nussinov R
Intramural Research Support Program-Science Applications International Corporation, Laboratory of Experimental and Computational Biology, National Cancer Institute, Building 469, Room 151, Frederick, MD 21702, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3139-44. doi: 10.1073/pnas.051399098.
Here we study the effect of point mutations in proteins on the redistributions of the conformational substates. We show that regardless of the location of a mutation in the protein structure and of its type, the observed movements of the backbone recur largely at the same positions in the structures. Despite the different interactions that are disrupted and formed by the residue substitution, not only are the conformations very similar, but the regions that move are also the same, regardless of their sequential or spatial distance from the mutation. This observation leads us to conclude that, apart from some extreme cases, the details of the interactions are not critically important in determining the protein conformation or in specifying which parts of the protein would be more prone to take on different local conformations in response to changes in the sequence. This finding further illustrates why proteins manifest a robustness toward many mutational events. This nonuniform distribution of the conformer population is consistently observed in a variety of protein structural types. Topology is critically important in determining folding pathways, kinetics, building block cutting, and anatomy trees. Here we show that topology is also very important in determining which regions of the protein structure will respond to sequence changes, regardless of the sequential or spatial location of the mutation.
在此，我们研究蛋白质中的点突变对构象亚态重新分布的影响。我们表明，无论突变在蛋白质结构中的位置及其类型如何，观察到的主链运动在很大程度上都在结构中的相同位置反复出现。尽管残基取代会破坏和形成不同的相互作用，但不仅构象非常相似，而且移动的区域也相同，无论它们与突变的序列或空间距离如何。这一观察结果使我们得出结论，除了一些极端情况外，相互作用的细节在决定蛋白质构象或指定蛋白质的哪些部分更易于响应序列变化而呈现不同的局部构象方面并非至关重要。这一发现进一步说明了蛋白质为何对许多突变事件具有稳健性。在各种蛋白质结构类型中都一致观察到构象异构体群体的这种非均匀分布。拓扑结构在决定折叠途径、动力学、构建模块切割和剖析树方面至关重要。在此我们表明，拓扑结构在决定蛋白质结构的哪些区域会响应序列变化方面也非常重要，无论突变的序列或空间位置如何。
