Department of Biochemistry , University of Zürich , 8057 Zürich , Switzerland.
J Phys Chem B. 2018 Dec 13;122(49):11072-11082. doi: 10.1021/acs.jpcb.8b05236. Epub 2018 Jul 17.
We present a simulation study of the early events of peptide dissociation from a fibril of the Alzheimer's Aβ42 peptide. The fibril consists of layers of two adjacent Aβ42 peptides each folded in an S-shaped structure which has been determined by solid state NMR spectroscopy of a monomorphic disease-relevant species. Multiple molecular dynamics runs (16 at 310 K and 15 at 370 K) were carried out starting from an 18-peptide protofibril for a cumulative sampling of about 15 μs. The simulations show structural stability of the fibrillar core and an overall increase in the twist to about 3 degrees. The N-terminal segment 1-14 is disordered in all peptides. At both ends of the fibril, the central segment 21-29, which includes part of the β strand, dissociates in some of the simulations. The β and β strands, residues 15-20 and 35-41, respectively, are structurally stable. The transient binding of the N-terminal stretch to the β strand of the adjacent peptide at the tip is likely to contribute to the arrest phase of the stop-and-go mechanism.
我们进行了一项关于阿尔茨海默病 Aβ42 肽从纤维中解离的早期事件的模拟研究。该纤维由两层相邻的 Aβ42 肽组成，每个肽都以 S 形结构折叠，这一结构已通过固态 NMR 光谱学确定，适用于单态疾病相关物种。我们进行了多次分子动力学模拟（310 K 下进行了 16 次，370 K 下进行了 15 次），从一个 18 肽原纤维开始，累积采样约 15 μs。模拟结果表明纤维核心结构稳定，整体扭曲度增加约 3 度。所有肽中的 N 端片段 1-14 均无规则。在纤维的两端，包括部分β链的中心片段 21-29，在一些模拟中会解离。β和β 链，分别对应残基 15-20 和 35-41，结构稳定。N 端延伸段与相邻肽β链在尖端的瞬时结合可能有助于停止-启动机制的阻滞相。
