The assembly of the β-amyloid peptide Aβ into toxic oligomers plays a significant role in the neurodegeneration associated with the pathogenesis of Alzheimer’s disease. Our laboratory has developed N-methylation as a tool to enable X-ray crystallographic studies of oligomers formed by macrocyclic β-hairpin peptides derived from Aβ. In this investigation, we set out to determine whether α-methylation could be used as an alternative to N-methylation in studying the oligomerization of a β-hairpin peptide derived from Aβ. α-Methylation permits the crystallographic assembly of a triangular trimer and ball-shaped dodecamer, resembling assemblies formed by the N-methylated homolog. Subtle differences are observed in the conformation of the α-methylated peptide when compared to the N-methylated homolog. Notably, α-methylation appears to promote a flatter and more extended β-sheet conformation than that of N-methylated β-sheets or a typical unmodified β-sheet. α-Methylation provides an alternative to N-methylation in X-ray crystallographic studies of oligomers formed by peptides derived from Aβ, with the attractive feature of preserving NH hydrogen-bond donors along the peptide backbone.

中文翻译：

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α-甲基化能够对源自 Aβ 的 β-发夹肽形成的寡聚组装体进行 X 射线晶体学观察


β-淀粉样肽 Aβ 组装成有毒的寡聚体在与阿尔茨海默病发病机制相关的神经退行性变中起重要作用。我们的实验室开发了 N-甲基化作为一种工具，可以对源自 Aβ 的大环 β-发夹肽形成的低聚物进行 X 射线晶体学研究。在这项研究中，我们着手确定 α-甲基化是否可以用作 N-甲基化的替代品，以研究源自 Aβ 的 β-发夹肽的寡聚化。α-甲基化允许三角形三聚体和球形十二聚体的晶体组装，类似于由 N-甲基化同源物形成的组装。与 N 甲基化同源物相比，α-甲基化肽的构象存在细微差异。值得注意的是，α-甲基化似乎比 N 甲基化的 β-折叠或典型的未修饰的 β 折叠更平坦、更延伸的 β 折叠构象。α-甲基化在由 Aβ 衍生肽形成的寡聚体的 X 射线晶体学研究中提供了 N-甲基化的替代方案，具有沿肽骨架保留 NH 氢键供体的诱人特征。