The Ability of an α-Aminoisobutyric Acid Residue to Promote Helical Folding in Oligopeptides

Abstract

Abstract In order to investigate the ability of an Aib residue to promote helical folding in oligopeptides, oligo(Leu)s containing an Aib residue were prepared by stepwise elongation and fragment condensation methods. The peptides prepared were the following: Boc–Aib–Leun–OBzl (n=3–6 and 9), Boc–Leun–Aib–OBzl (n=3–6 and 9), Boc–Leu3–Aib–Leu3–OBzl, Boc–Leu4–Aib–Leu4–OBzl, Boc–Leu8–Aib–Leu4–OBzl, Boc–Leu4–Aib–Leu8–OBzl, and Boc–Leu8–Aib–Leu8–OBzl. The IR absorption conformational analyses of Boc–Aib–Leun–OBzl (n=3–6) in dichloromethane have shown the occurrence of incipient helical structures (α- or 310-helixes) formed by one, two, three, and so forth i→i–4 or i→i–3 hydrogen-bonding patterns. All the peptides except Boc–Aib–Leu9–OBzl and Boc–Leun–Aib–OBzl (n=6 and 9) have also shown helical structures (α- or 310-helixes), indicating the great ability of an Aib residue to promote helical folding in peptides. This is in remarkable contrast with the fact that homologous oligo(Leu) counterparts have β-sheet structures. The solubility properties of the peptides were in good agreement with those speculated from their conformations. The initiation and stabilization mechanism of helical folding in peptides has been illustrated schematically and attributed to the restriction of the values of the backbone dihedral angles φ and ψ of an Aib residue due to steric hindrance, followed by the restriction of the values of φ and ψ of other amino acid residues due to hydrogen bonds initiated by the Aib residue. The great ability of an Aib residue to promote helical folding in peptides also suggests that the restriction of the values of the backbone dihedral angles φ and ψ (right-handed α-helix: φ=−57°, ψ=−47°) of an amino acid residue in peptide chains is one of important initiation mechanisms of α-helical folding in natural proteins. The implication of the new findings for the study of proteins containing Aib residues is presented on the basis of the stabilizing efficacy of Aib residues on helical regions of proteins.