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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Monomer adds to preformed structured oligomers of A beta-peptides by a two-stage dock-lock mechanism
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Monomer adds to preformed structured oligomers of A beta-peptides by a two-stage dock-lock mechanism

机译：单体通过两步码头锁定机制添加到预制的Aβ肽结构化低聚物中

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摘要

Nonfibrillar soluble oligomers, which are intermediates in the transition from monomers to amyloid fibrils, may be the toxic species in Alzheimer's disease. To monitor the early events that direct assembly of amyloidogenic peptides we probe the dynamics of formation of (A beta(16-22))(n) by adding a monomer to a preformed (A beta(16-22))(n-1) (n = 4-6) oligomer in which the peptides are arranged in an antiparallel beta-sheet conformation. All atom molecular dynamics simulations in water and multiple long trajectories, for a cumulative time of 6.9 mu s, show that the oligomer grows by a two-stage dock-lock mechanism. The largest conformational change in the added disordered monomer occurs during the rapid (approximate to 50 ns) first dock stage in which the beta-strand content of the monomer increases substantially from a low initial value. In the second slow-lock phase, the monomer rearranges to form in register antiparallel structures. Surprisingly, the mobile structured oligomers undergo large conformational changes in order to accommodate the added monomer. The time needed to incorporate the monomer into the fluid-like oligomer grows even when n = 6, which suggests that the critical nucleus size must exceed six. Stable antiparallel structure formation exceeds hundreds of nanoseconds even though frequent interpeptide collisions occur at elevated monomer concentrations used in the simulations. The dock-lock mechanism should be a generic mechanism for growth of oligomers of amyloidogenic peptides.
机译：非原纤维可溶的低聚物是从单体到淀粉样原纤维转变的中间体，可能是阿尔茨海默氏病的有毒物质。为了监测指导淀粉样蛋白生成肽组装的早期事件，我们通过向预先形成的（A beta（16-22））（n-1）中添加单体来探索（A beta（16-22））（n）形成的动力学。 （n = 4-6）个寡聚体，其中肽以反平行的β-折叠构象排列。在水和多条长轨道上进行的所有原子分子动力学模拟（累积时间为6.9μs）表明，低聚物是通过两阶段对接锁定机制生长的。添加的无序单体中最大的构象变化发生在快速（约50 ns）的第一对接阶段，其中单体的β链含量从较低的初始值开始显着增加。在第二个慢锁相中，单体重排形成反平行结构。出人意料的是，可移动的结构低聚物经历了大的构象变化，以适应所添加的单体。即使当n = 6时，将单体掺入类流体低聚物所需的时间也会增加，这表明临界核尺寸必须超过六个。即使在模拟中使用的单体浓度升高时，频繁发生肽间碰撞，稳定的反平行结构形成也会超过数百纳秒。码头锁定机制应该是淀粉样蛋白生成肽寡聚体生长的通用机制。

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