Conformer-Specific Spectroscopy and IR-Induced Isomerization of a Model γ-Peptide: Ac-γ⁴-Phe-NHMe

Area of Science:

• Physical Chemistry
• Spectroscopy
• Computational Chemistry

Background:

• Understanding peptide and protein folding is crucial for comprehending biological function and disease.
• γ-Peptides offer unique structural properties compared to natural α-peptides, making them interesting models for folding studies.
• Conformational preferences in the gas phase provide intrinsic structural information, free from solvent effects.

Purpose of the Study:

• To investigate the intrinsic conformational preferences of the capped γ-peptide Ac-γ⁴-Phe-NHMe (γ⁴F) in the gas phase.
• To compare the conformational landscape of γ⁴F with its γ²F counterpart.
• To elucidate the role of side-chain substitution on peptide folding pathways.

Main Methods:

• Single-conformation infrared (IR) and ultraviolet (UV) spectroscopy under jet-cooled conditions.
• IR population transfer spectroscopy to determine conformer fractional abundances.
• Force field and density functional theory (DFT) calculations to map conformational potential energy surfaces.

Main Results:

• Four distinct conformers of γ⁴F were identified: three forming nine-membered hydrogen-bonded rings (C9) with varied phenyl ring orientations, and one forming a strained seven-membered amide-stacked ring (S7).
• The S7 conformer is analogous to the amide-stacked conformer previously observed in γ²F.
• Calculations indicate that the phenyl ring in γ⁴F prefers orientations that facilitate NH···π interactions, contrasting with γ²F where it avoids interactions with the C═O group.
• A significant energy barrier (~42 kJ/mol) separates the C9 and amide-stacked conformational families, suggesting distinct folding pathways.

Conclusions:

• The study reveals the key conformational states accessible to γ⁴F in isolation, highlighting the influence of γ-substitution on folding.
• The observed conformational landscape and energy barriers provide a model for understanding competing folding pathways in peptides and proteins.
• The findings contribute to the broader understanding of molecular self-assembly and the design of novel peptide structures.