12/14/14-Helix Formation in 2:1 α/β-Hybrid Peptides Containing Bicyclo[2.2.2]octane Ring Constraints

The highly constrained beta-amino acid ABOC induces different types of helices in beta urea and 1:1 alpha/beta amide oligomers. The latter can adopt 11/9- and 18/16-helical folds depending on the chain length in solution. Short peptides alternating proteinogenic alpha-amino acids and ABOC in a 2: 1 alpha/beta repeat pattern adopted an unprecedented and stable 12/14/14-helix. The structure was established through extensive NMR, molecular dynamics, and IR studies. While the 1: 1 alpha-AA/ABOC helices diverged from the canonical alpha-helix, the helix formed by the 9-mer 2: 1 alpha/beta-peptide allowed the projection of the alpha-amino acid side chains in a spatial arrangement according to the alpha-helix. Such a finding constitutes an important step toward the conception of functional tools that use the ABOC residue as a potent helix inducer for biological applications.