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Phys Rev Lett. 2013 Apr 19;110(16):168103. doi: 10.1103/PhysRevLett.110.168103. Epub 2013 Apr 17.
By extended atomistic simulations in explicit solvent and bias-exchange metadynamics, we study the aggregation process of 18 chains of the C-terminal segment of amyloid-β, an intrinsically disordered protein involved in Alzheimer's disease and prone to form fibrils. Starting from a disordered aggregate, we are able to observe the formation of an ordered nucleus rich in beta sheets. The rate limiting step in the nucleation pathway involves crossing a barrier of approximately 40 kcal/mol and is associated with the formation of a very specific interdigitation of the side chains belonging to different sheets. This structural pattern is different from the one observed experimentally in a microcrystal of the same system, indicating that the structure of a "nascent" fibril may differ from the one of an "extended" fibril.
通过在显式溶剂和偏置交换元动力学中的扩展原子模拟，我们研究了淀粉样蛋白-β（一种参与阿尔茨海默病且易于形成原纤维的无规卷曲蛋白）C 端片段的 18 条链的聚集过程。从无规聚集物开始，我们能够观察到富含β片层的有序核的形成。成核途径中的限速步骤涉及跨越约 40 千卡/摩尔的势垒，与不同片层的侧链的非常特定的交错形成有关。这种结构模式与同一体系微晶中观察到的实验结构不同，表明“初生”原纤维的结构可能与“延伸”原纤维的结构不同。
