Solid state and solution conformations of a hybrid αγααγα hexapeptide. Characterization of a backbone expanded analog of the α-polypeptide 3₁₀-helix

Abstract

The stereochemically constrained amino acid residue gabapentin (1-(aminomethyl)cyclohexaneacetic acid, Gpn) has been incorporated into a host α-peptide sequence. The structure of a hybrid αγααγα peptide, Boc-Leu-Gpn-Aib-Leu-Gpn-Aib-OMe in crystals reveals a continuous helical conformation stabilized by three intramolecular 4 →1 C₁₂ hydrogen bonds across the αγ/αγ segments and one C₁₀ hydrogen bond across the central segment. This conformation corresponds to an expanded analog of the canonical all-α polypeptide 3₁₀-helix, with insertion of two additional backbone atoms at each γ residue. Solvent dependence of NH chemical shifts in CDCl₃ solution are consistent with conformation in which the NH groups of Aib (3), Leu (4), Gpn (5), and Aib (6) are hydrogen bonded, a feature observed in the solid state. The nonsequential NOEs between Gpn (2) N↔H Leu (4) NH and Gpn (2) NH ↔Gpn (5) NH support the presence of additional conformations in solution. Temperature-dependent line broadening of NH resonances confirms the occurrence of rapid exchange between multiple conformations at room temperature. Two conformational models which rationalize the observed nonsequential NOEs are presented, both of which contain three hydrogen bonds and are consistent with the known stereochemical preferences of the Gpn residue.