Expanding the Peptide β-Turn in αγ Hybrid Sequences: 12 Atom Hydrogen Bonded Helical and Hairpin Turns

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 Cγ−Cβ (θ1) and Cβ−Cα (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.