Transient Secondary and Tertiary Structure Formation Kinetics in the Intrinsically Disordered State of α-Synuclein from Atomistic Simulations
Transient Secondary and Tertiary Structure Formation Kinetics in the Intrinsically Disordered State of α-Synuclein from Atomistic Simulations
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DOI：
10.1002/cphc.201800504
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发表时间：
2018-10-05
期刊：
影响因子：
2.9
通讯作者：
Grubmueller, Helmut
中科院分区：
文献类型：
--
作者：
Graen, Timo;Klement, Reinhard;Grubmueller, Helmut
在不存在稳定折叠的情况下，瞬时二级结构动力学定义了原型和与之相关的固有无序蛋白（IDP）α-突触核蛋白（aS）的天然状态。在这里，我们调查动力学防止有序和可能致病的β-折叠聚集。有趣的是，瞬时β-折叠经常在亚s时间尺度上精确地在aS淀粉样蛋白原纤维中观察到的位置形成。形成动力学与快速二级结构解离速率竞争，从而解释了低二级结构含量。快速的二级结构解离时间与三级结构重排的动力学非常相似。这些发现表明，快速解离动力学减慢了AS聚集的构象选择过程，这可能是控制IDPs聚集动力学的一般机制。
In the absence of a stable fold, transient secondary structure kinetics define the native state of the prototypical and pharmacologically relevant intrinsically disordered protein (IDP) alpha-Synuclein (aS). Here, we investigate kinetics preventing ordering and possibly pathogenic beta-sheet aggregation. Interestingly, transient beta-sheets form frequently at sub s time scales precisely at the positions observed in aS amyloid fibrils. The formation kinetics competes with rapid secondary structure dissociation rates, thus explaining the low secondary structure content. The fast secondary structure dissociation times are very similar to the dynamics of tertiary structure rearrangements. These findings suggest that the fast dissociation kinetics slows down conformational selection processes for aS aggregation, which may be a general mechanism controlling the aggregation kinetics of IDPs.