Solid state and solution conformations of a hybrid αγααγα hexapeptide. Characterization of a backbone expanded analog of the α‐polypeptide 3 10 ‐helix

The stereochemically constrained γ 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 C 12 hydrogen bonds across the αγ/αγ segments and one C 10 hydrogen bond across the central αα segment. This conformation corresponds to an expanded analog of the canonical all‐α polypeptide 3 10 ‐helix, with insertion of two additional backbone atoms at each γ residue. Solvent dependence of NH chemical shifts in CDCl 3 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) NH ↔ 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. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 85:759–771, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com