α-Methylation Enables the X-ray Crystallographic Observation of Oligomeric Assemblies Formed by a β-Hairpin Peptide Derived from Aβ

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 -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 -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 -methylated homolog. Subtle differences are observed in the conformation of the α-methylated peptide when compared to the -methylated homolog. Notably, α-methylation appears to promote a flatter and more extended β-sheet conformation than that of -methylated β-sheets or a typical unmodified β-sheet. α-Methylation provides an alternative to -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.