Impact of Strand Edge N-Amination on the Stability of a Parallel β-Hairpin Fold

Peptide backbone N-amination has emerged as a useful strategy to stabilize antiparallel β-sheet structure. Here, we used circular dichroism and NMR to evaluate the impact of amide-to-hydrazide substitution on the folded population of a parallel β-hairpin model. Outer-edge N-amination was well tolerated and resulted in enhanced stability relative to N-methylation. High-resolution NMR structures confirmed that the α-hydrazino acid residues adopt canonical parallel β-strand torsions that are compatible with the formation of intraresidue C6 hydrogen bonds involving the hydrazide NH₂ group.