Conformer-Specific Spectroscopy and IR-Induced Isomerization of a Model γ-Peptide: Ac-γ-Phe-NHMe.

Single-conformation IR and UV spectroscopy of the prototypical capped γ-peptide Ac-γ-Phe-NHMe (γF) was carried out under jet-cooled conditions in the gas phase in order to understand its innate conformational preferences in the absence of a solvent. We obtained conformer-specific IR and UV spectra and compared the results with calculations to make assignments and explore the differences between the γ- and γ-substituted molecules. We found four conformers of γF in our experiment. Three conformers form nine-membered hydrogen-bonded rings (C9) enclosed by an NH···O═C H-bond but differing in their phenyl ring positions (a, g+, and g-). The fourth conformer forms a strained seven-membered hydrogen-bonded ring in which the amide groups lie in a nominally anti-parallel arrangement stacked on top of one another (labeled S7). This conformer is a close analogue of the amide-stacked conformer (S) found previously in γF, in which the Phe side chain is substituted at the γ position, Ac-γ2-Phe-NHMe ( 14243-14245). IR population transfer spectroscopy was used to determine the fractional abundances of the γF conformers in the expansion. A combination of force field and density functional theory calculations is used to map out the conformational potential energy surfaces for γF and compare it with its γF counterpart. Based on this analysis, the phenyl ring prefers to take up structures that facilitate NH···π interactions in γF or avoid phenyl interactions with the C═O group in γF. The disconnectivity graph for γF reveals separate basins associated with the C9 and amide-stacked conformational families, which are separated by a barrier of about 42 kJ/mol. The overall shape of the potential energy surface bears a resemblance to peptides and proteins that have a misfolding pathway that competes with the formation of the native structure.