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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >α-Helix folding in the presence of structural constraints
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α-Helix folding in the presence of structural constraints

机译：在存在结构约束的情况下进行α-螺旋折叠

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摘要

We have investigated the site-specific folding kinetics of a photoswitchable cross-linked α-helical peptide by using single 13C = 18O isotope labeling together with time-resolved IR spectroscopy. We observe that the folding times differ from site to site by a factor of eight at low temperatures (6°C), whereas at high temperatures (45°C), the spread is considerably smaller. The trivial sum of the site signals coincides with the overall folding signal of the unlabeled peptide, and different sites fold in a noncooperative manner. Moreover, one of the sites exhibits a decrease of hydrogen bonding upon folding, implying that the unfolded state at low temperature is not unstructured. Molecular dynamics simulations at low temperature reveal a stretched-exponential behavior which originates from parallel folding routes that start from a kinetically partitioned unfolded ensemble. Different metastable structures (i.e., traps) in the unfolded ensemble have a different ratio of loop and helical content. Control simulations of the peptide at high temperature, as well as without the cross-linker at low temperature, show faster and simpler (i.e., single-exponential) folding kinetics. The experimental and simulation results together provide strong evidence that the rate-limiting step in formation of a structurally constrained α-helix is the escape from heterogeneous traps rather than the nucleation rate. This conclusion has important implications for an α-helical segment within a protein, rather than an isolated α-helix, because the cross-linker is a structural constraint similar to those present during the folding of a globular protein.
机译：我们已经通过使用单一的 13 C = 18 O同位素标记以及时间分辨红外光谱研究了光可切换交联的α-螺旋肽的位点特异性折叠动力学。我们观察到，在低温（6°C）下，每个位置的折叠时间相差八倍，而在高温（45°C）下，展开的距离要小得多。位点信号的琐碎总和与未标记肽的整体折叠信号一致，并且不同位点以非合作方式折叠。而且，其中一个位点在折叠时表现出氢键的减少，这意味着在低温下的未折叠状态不是非结构化的。低温下的分子动力学模拟揭示了拉伸指数行为，该行为源自平行折叠路线，该路线从动力学分区的未折叠整体开始。展开的集合中不同的亚稳结构（即陷阱）具有不同的环含量和螺旋含量。在高温下以及在低温下没有交联剂的情况下，肽的对照模拟显示出更快和更简单的折叠动力学（即单指数）。实验和模拟结果共同提供了有力的证据，表明结构受约束的α-螺旋形成过程中的限速步骤是从异质陷阱中逃脱，而不是成核速率。该结论对蛋白质内的α螺旋片段（而不是分离的α螺旋）具有重要意义，因为交联剂是一种结构性约束，类似于球形蛋白质折叠过程中存在的约束。

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