Out-of-Register Aβ42 Assemblies as Models for Neurotoxic Oligomers and Fibrils

We propose a variant
of the recently found S-shaped Aβ1–42-motif
that is characterized by out-of-register
C-terminal β-strands. We show that chains with this structure
can form not only fibrils that are compatible with the NMR signals
but also barrel-shaped oligomers that resemble the ones formed by
the much smaller cylindrin peptides. By running long all-atom molecular
dynamics simulations at physiological temperatures with an explicit
solvent, we study the stability of these constructs and show that
they are plausible models for neurotoxic oligomers. After analyzing
the transitions between different assemblies, we suggest a mechanism
for amyloid formation in Alzheimer’s disease.

本课题组提出了一种新型的S形Aβ1–42基序变体，其特征为非规整的C端β-折叠链。研究表明，此类结构不仅能够形成与核磁共振信号相吻合的纤维，还能够形成类似由较小圆柱肽形成的桶状寡聚体。通过在生理温度下进行长程全原子分子动力学模拟并采用显式溶剂，我们探讨了这些结构的稳定性，并证实它们是神经毒性寡聚体的合理模型。在分析不同组装体之间的转换后，我们提出了阿尔茨海默病中淀粉样蛋白形成的一种机制。