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首页> 外文期刊>Journal of Molecular Biology >Role of native topology investigated by multiple unfolding simulations of four SH3 domains.
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Role of native topology investigated by multiple unfolding simulations of four SH3 domains.

机译：通过四个SH3域的多次展开仿真研究了本机拓扑的作用。

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摘要

The relative importance of amino acid sequence and native topology in the unfolding process of two SH3 domains and two circular permutants was investigated by 120 molecular dynamics runs at 375 K for a total simulation time of 0.72 micros. The alpha-spectrin (aSH3) and src SH3 (sSH3) domains, which have the same topology and a sequence identity of only 34%, show similar unfolding pathways. The disappearance of the three-stranded antiparallel beta-sheet is the last unfolding event, in agreement with a large repertoire of kinetic data derived from point mutations as well as glycine insertions and disulfide crosslinks. Two alternative routes of beta-sheet unfolding have emerged from the analysis of the trajectories. One is statistically preferred in aSH3 (n-src loop breaks before distal hair-pin) and the inverse in sSH3. An elongation of the beta2-beta3 hairpin was observed during the unfolding of sSH3 at 375 K and in 300 K simulations started from the putative transition state of sSH3 in accord with unusual kinetic data for point mutations at the n-src loop. The change of connectivity in the permutants influenced the sequence of unfolding events mainly at the permutation site. Regions where the connectivity remained unaffected showed the same chronology of contact disappearance. Taken together with previous folding simulations of two designed three-stranded antiparallel beta-sheet peptides, these results indicate that, at least for small beta-sheet proteins, the folding mechanism is primarily defined by the native state topology, whilst specific interactions determine the statistically predominant folding route.
机译：氨基酸序列和天然拓扑结构在两个SH3域和两个圆形置换子展开过程中的相对重要性，通过在375 K下运行的120个分子动力学进行了研究，总模拟时间为0.72 micros。具有相同拓扑结构且序列同一性仅为34％的alpha-spectrin（aSH3）和src SH3（sSH3）域显示了相似的展开途径。三链反平行β-折叠的消失是最后一个展开的事件，这与从点突变以及甘氨酸插入和二硫键交联得到的大量动力学数据一致。从轨迹分析中得出了两种不同的β-折叠展开途径。从统计学上讲，aSH3（远端发夹之前的n-src环断裂）和sSH3的倒数在统计学上是优选的。在375 K的sSH3展开过程中观察到beta2-beta3发夹的延长，在300 K的模拟中，从sSH3的假定过渡态开始，这与n-src环上点突变的异常动力学数据一致。置换中连接性的变化主要影响置换位点的展开事件的顺序。连通性未受影响的区域显示出相同的接触消失时间顺序。结合先前对两种设计的三链反平行β-折叠肽的折叠模拟，这些结果表明，至少对于小β-折叠蛋白，折叠机制主要是由天然状态拓扑定义的，而特定的相互作用在统计学上决定了折叠路线占主导地位。

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