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Cyclic Constraints on Conformational Flexibility in γ‑Peptides: Conformation Specific IR and UV Spectroscopy

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journal contribution
posted on 27.11.2013, 00:00 by Patrick S. Walsh, Ryoji Kusaka, Evan G. Buchanan, William H. James, Brian F. Fisher, Samuel H. Gellman, Timothy S. Zwier
Single-conformation spectroscopy has been used to study two cyclically constrained and capped γ-peptides: Ac-γACHC-NHBn (hereafter γACHC, Figure 1a), and Ac-γACHCACHC-NHBn (γγACHC, Figure 1b), under jet-cooled conditions in the gas phase. The γ-peptide backbone in both molecules contains a cyclohexane ring incorporated across each Cβ-Cγ bond and an ethyl group at each Cα. This substitution pattern was designed to stabilize a (g+, g+) torsion angle sequence across the Cα–Cβ–Cγ segment of each γ-amino acid residue. Resonant two-photon ionization (R2PI), infrared–ultraviolet hole-burning (IR–UV HB), and resonant ion-dip infrared (RIDIR) spectroscopy have been used to probe the single-conformation spectroscopy of these molecules. In both γACHC and γγACHC, all population is funneled into a single conformation. With RIDIR spectra in the NH stretch (3200–3500 cm–1) and amide I/II regions (1400–1800 cm–1), in conjunction with theoretical predictions, assignments have been made for the conformations observed in the molecular beam. γACHC forms a single nearest-neighbor C9 hydrogen-bonded ring whereas γγACHC takes up a next-nearest-neighbor C14 hydrogen-bonded structure. The gas-phase C14 conformation represents the beginning of a 2.614-helix, suggesting that the constraints imposed on the γ-peptide backbone by the ACHC and ethyl groups already impose this preference in the gas-phase di-γ-peptide, in which only a single C14 H-bond is possible, constituting one full turn of the helix. A similar conformational preference was previously documented in crystal structures and NMR analysis of longer γ-peptide oligomers containing the γACHC subunit [Guo, L., et al. Angew. Chem. Int. Ed. 2011, 50, 5843−5846]. In the gas phase, the γACHC-H2O complex was also observed and spectroscopically interrogated in the molecular beam. Here, the monosolvated γACHC retains the C9 hydrogen bond observed in the bare molecule, with the water acting as a bridge between the C-terminal carbonyl and the π-cloud of the UV chromophore. This is in contrast to the unconstrained γ-peptide-H2O complex, which incorporates H2O into both C9 and amide-stacked conformations.