Peptide design using α,β-dehydro amino acids: from β-turns to helical hairpins

Abstract

Incorporation of α,β-dehydrophenylalanine (ΔPhe) residue in peptides induces folded conformations: β-turns in short peptides and 3₁₀-helices in larger ones. A few exceptions-namely, α-helix or flat β-bend ribbon structures-have also been reported in a few cases. The most favorable conformation of ΔPhe residues are (Φ,ψ) ~ (−60°, −30°), (−60°, 150°), (80°, 0°) or their enantiomers. ΔPhe is an achiral and planar residue. These features have been exploited in designing ΔPhe zippers and helix-turn-helix motifs. ΔPhe can be incorporated in both right and left-handed helices. In fact, consecutive occurrence of three or more ΔPhe amino acids induce left-handed screw sense in peptides containing L-amino acids. Weak interactions involving the ΔPhe residue play an important role in molecular association. The C-H^...O=C hydrogen bond between the ΔPhe side-chain and backbone carboxyl moiety, π-π stacking interactions between ΔPhe side chains belonging to enantiomeric helices have shown to stabilize folding. The unusual capability of a ΔPhe ring to form the hub of multicentered interactions namely, a donor in aromatic C-H^...π and C-H^...O=C and an acceptor in a CH₃^...π interaction suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures.