Conformer-Specific Spectroscopy and IR-Induced Isomerization of a Model gamma-Peptide: Ac-gamma(4)-Phe-NHMe

Single-conformation IR and UV spectroscopy of the prototypical capped gamma-peptide Ac-gamma(4)-Phe-NHMe (gamma F-4) 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 gamma(2)-and gamma(4)-substituted molecules. We found four conformers of gamma F-4 in our experiment. Three conformers form nine-membered hydrogen-bonded rings (C9) enclosed by an NH center dot center dot center dot 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 gamma F-2, in which the Phe side chain is substituted at the gamma(2) position, Ac-gamma 2-Phe-NHMe (J. Am. Chem. Soc. 2009, 131, 14243-14245). IR population transfer spectroscopy was used to determine the fractional abundances of the gamma F-4 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 gamma F-4 and compare it with its gamma F-2 counterpart. Based on this analysis, the phenyl ring prefers to take up structures that facilitate NH center dot center dot center dot pi interactions in gamma F-4 or avoid phenyl interactions with the C=O group in gamma F-2. The disconnectivity graph for gamma F-4 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.