Expanding the peptide β-turn in αγ hybrid sequences: 12 atom hydrogen bonded helical and hairpin turns

Abstract

Hybrid peptide segments containing contiguous α and γ amino acid residues can form C₁₂ hydrogen bonded turns which may be considered as backbone expanded analogues of C₁₀ (β-turns) found in αα segments. Exploration of the regular hydrogen bonded conformations accessible for hybrid αγ sequences is facilitated by the use of a stereochemically constrained γ amino acid residue gabapentin (1-aminomethylcyclohexaneacetic acid, Gpn), in which the two torsion angles about C^γ-C^β (θ₁) and C^β-C^α (θ₂) are predominantly restricted to gauche conformations. The crystal structures of the octapeptides Boc-Gpn-Aib-Gpn-Aib-Gpn-Aib-Gpn-Aib-OMe (1) and Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-Val-OMe (2) reveal two distinct conformations for the Aib-Gpn segment. Peptide 1 forms a continuous helix over the Aib(2)-Aib(6) segment, while the peptide 2 forms a β-hairpin structure stabilized by four cross-strand hydrogen bonds with the Aib-Gpn segment forming a nonhelical C₁₂ turn. The robustness of the helix in peptide 1 in solution is demonstrated by NMR methods. Peptide 2 is conformationally fragile in solution with evidence of β-hairpin conformations being obtained in methanol. Theoretical calculations permit delineation of the various C₁₂ hydrogen bonded structures which are energetically feasible in αγ and γα sequences.