α‑Methylation\nEnables the X‑ray\nCrystallographic Observation of Oligomeric Assemblies Formed by a\nβ‑Hairpin Peptide Derived from Aβ

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