Different circular permutations produced different folding nuclei in proteins: A computational study
Different circular permutations produced different folding nuclei in proteins: A computational study
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DOI：
10.1006/jmbi.2000.4375
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发表时间：
2001-02-09
影响因子：
5.6
通讯作者：
Shakhnovich, EI
中科院分区：
文献类型：
--
作者：
Li, L;Shakhnovich, EI
关于环状排列对蛋白质过渡态/折叠核的影响的研究很多，有时不同的蛋白质和排列得出的结论相互矛盾。为了澄清这一重要问题，我们研究了带侧链的晶格蛋白模型的两种圆形排列。这两种排列序列本质上与原始（野生型）序列具有相同的原生状态。圆形排列体1在野生型序列的折叠核上切割。结果，排列体有一个完全不同的细胞核，折叠速度比野生型慢。相反，圆形排列体2涉及在野生型过渡状态下的非结构化部位的切口，并且野生型细胞核在排列体中大部分保留。此外，置换体2同时显示两态和多态折叠，偶尔会填充类似原生的中间状态。野生型和排列突变体1都没有类似的中间体，并且都以明显的两态方式折叠。令人惊讶的是，排列体2的折叠速度与野生型相同。置换体2中的中间体是由原生和非原生相互作用稳定的，不能简单地分为通路上或通路外。因此，我们建议在将实验数据归因于通路内或通路外中间体时要谨慎。最后，我们的工作阐明了α -谱蛋白SH3、凝乳胰蛋白酶抑制剂2和β -乳球蛋白的结果，并支持了通过循环排列定位真实蛋白质潜在成核位点的实验工作中的一个关键假设。(C) 2001学术出版社。
There have been many studies about the effect of circular permutation on the transition state/folding nucleus of proteins, with sometimes conflicting conclusions from different proteins and permutations. To clarify this important issue, we have studied two circular permutations of a lattice protein model with side-chains. Both permuted sequences have essentially the same native state as the original (wild-type) sequence. Circular permutant 1 cuts at the folding nucleus of the wild-type sequence. As a result, the permutant has a drastically different nucleus and folds more slowly than wild-type. In contrast, circular permutant 2 involves an incision at a site unstructured in the wild-type transition state, and the wild-type nucleus is largely retained in the permutant. In addition, permutant 2 displays both two-state and multi-state folding, with a nativelike intermediate state occasionally populated. Neither the wild-type nor permutant 1 has a similar intermediate, and both fold in an apparently two-state manner. Surprisingly, permutant 2 folds at a rate identical with that of the wild-type. The intermediate in permutant 2 is stabilised by native and non-native interactions, and cannot be classified simply as on or off-pathway. So we advise caution in attributing experimental data to on or off-pathway intermediates. Finally, our work illuminates the results on alpha -spectrin SH3, chymotrypsin inhibitor 2 and beta -lactoglobulin, and supports a key assumption in the experimental efforts to locate potential nucleation sites of real proteins via circular permutations. (C) 2001 Academic Press.