Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom.
J Comput Chem. 2010 Nov 30;31(15):2689-701. doi: 10.1002/jcc.21562.
Nonoverlapping closed loops of around 25-35 amino acids formed via nonlocal interactions at the loop ends have been proposed as an important unit of protein structure. This hypothesis is significant as such short loops can fold quickly and so would not be bound by the Leventhal paradox, giving insight into the possible nature of the funnel in protein folding. Previously, these closed loops have been identified either by sequence analysis (conservation and autocorrelation) or studies of the geometry of individual proteins. Given the potential significance of the closed loop hypothesis, we have explored a new strategy for determining closed loops from the insertions identified by the structural alignment of proteins sharing the same overall fold. We determined the locations of the closed loops in 37 pairs of proteins and obtained excellent agreement with previously published closed loops. The relevance of NMR structures to closed loop determination is briefly discussed. For cytochrome c, cytochrome b(562) and triosephophate isomerase, independent folding units have been determined on the basis of hydrogen exchange experiments and misincorporation proton-alkyl exchange experiments. The correspondence between these experimentally derived foldons and the theoretically derived closed loops indicates that the closed loop hypothesis may provide a useful framework for analyzing such experimental data.
已经提出，通过在环末端的非局部相互作用形成的大约 25-35 个氨基酸的非重叠封闭环是蛋白质结构的一个重要单元。这个假设很重要，因为这样的短环可以快速折叠，因此不会受到莱文塔尔悖论的限制，从而深入了解蛋白质折叠中可能的漏斗性质。以前，这些封闭环要么通过序列分析（保守性和自相关性），要么通过个别蛋白质的几何形状研究来识别。鉴于封闭环假说的潜在重要性，我们探索了一种从共享相同整体折叠的蛋白质的结构比对中识别出的插入物来确定封闭环的新策略。我们确定了 37 对蛋白质中封闭环的位置，并与以前发表的封闭环得到了很好的一致性。简要讨论了 NMR 结构与封闭环确定的相关性。对于细胞色素 c、细胞色素 b（562）和磷酸丙糖异构酶，已经基于氢交换实验和错误掺入质子-烷基交换实验确定了独立的折叠单元。这些实验衍生的折叠单元与理论上推导的封闭环之间的对应关系表明，封闭环假说可能为分析此类实验数据提供一个有用的框架。
