The Design of α/β-Peptides: Study on Three-Residue Turn Motifs and the Influence of Achiral Glycine on Helix and Turn

Abstract

Novel three-residue helix-turn secondary structures, nucleated by a helix at the N terminus, were generated in peptides that have 'β-Caa-L-Ala-L-Ala,' 'β-Caa-L-Ala-γ-Caa,' and 'β-Caa-L-Ala-δ-Caa' (in which β-Caa is C-linked carbo-β-amino acid, γ-Caa is C-linked carbo-γ-amino acid, and δ-Caa is C-linked carbo-δ-amino acid) at the C terminus. These turn structures are stabilized by 12-, 14-, and 15-membered (mr) hydrogen bonding between NH(i)/CO(i+2) (i+2 is the last residue in the peptide) along with a 7-mr hydrogen bond between CO(i)/NH(i+2). In addition, a series of α/β-peptides were designed and synthesized with alternating glycine (Gly) and (S)-β-Caa to study the influence of an achiral α-residue on the helix and helix-turn structures. In contrast to previous results, the three 'β-α-β' residues at the C terminus (α-residue being Gly) are stabilized by only a 13-mr forward hydrogen bond, which resembles an α-turn. Extensive NMR spectroscopic and molecular dynamics (MD) studies were performed to support these observations. The influence of chirality and side chain is also discussed.