Conformer-Specific Spectroscopy and IR-Induced Isomerization of a Model γ-Peptide: Ac-γ 4 -Phe-NHMe.

Single-conformation IR and UV spectroscopy of the prototypical capped γ-peptide Ac-γ 4 -Phe-NHMe (γ 4 F) 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 2 - and γ 4 -substituted molecules. We found four conformers of γ 4 F 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 γ 2 F, in which the Phe side chain is substituted at the γ 2 position, Ac-γ2-Phe-NHMe ( J. Am. Chem. Soc. 2009, 131, 14243-14245). IR population transfer spectroscopy was used to determine the fractional abundances of the γ 4 F 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 γ 4 F and compare it with its γ 2 F counterpart. Based on this analysis, the phenyl ring prefers to take up structures that facilitate NH···π interactions in γ 4 F or avoid phenyl interactions with the C═O group in γ 2 F. The disconnectivity graph for γ 4 F 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.