Inherent Conformational Preferences of Ac-Gln-Gln-NHBn: Sidechain Hydrogen Bonding Supports a ß-Turn in the Gas Phase.

Gas-phase single-conformation spectroscopy is used to study Ac-Gln-Gln-NHBn in order to probe the interplay between sidechain hydrogen bonding and backbone conformational preferences. This small, amide-rich peptide offers many possibilities for backbone-backbone, sidechain-backbone, and sidechain-sidechain interactions. The major conformer observed experimentally features a type-I ß-turn with a canonical 10-membered ring C=O-H-N hydrogen bond between backbone amide groups. In addition, the C=O group of each Gln sidechain participates in a seven-membered ring hydrogen bond with the backbone NH of the same residue. Thus, sidechain hydrogen-bonding potential is satisfied in a manner that is consistent with and stabilizes the ß-turn secondary structure. This turn-forming propensity may be relevant to pathogenic amyloid formation by polyglutamine segments in human proteins.

Conformation-specific spectroscopy of capped glutamine-containing peptides: role of a single glutamine residue on peptide backbone preferences.

The conformational preferences of a series of short, aromatic-capped, glutamine-containing peptides have been studied under jet-cooled conditions in the gas phase. This work seeks a bottom-up understanding of the role played by glutamine residues in directing peptide structures that lead to neurodegenerative diseases. Resonant ion-dip infrared (RIDIR) spectroscopy is used to record single-conformation infrared spectra in the NH stretch, amide I and amide II regions. Comparison of the experimental spectra with the predictions of calculations carried out at the DFT M05-2X/6-31+G(d) level of theory lead to firm assignments for the H-bonding architectures of a total of eight conformers of four molecules, including three in Z-Gln-OH, one in Z-Gln-NHMe, three in Ac-Gln-NHBn, and one in Ac-Ala-Gln-NHBn. The Gln side chain engages actively in forming H-bonds with nearest-neighbor amide groups, forming C8 H-bonds to the C-terminal side, C9 H-bonds to the N-terminal side, and an amide-stacked geometry, all with an extended (C5) peptide backbone about the Gln residue. The Gln side chain also stabilizes an inverse γ-turn in the peptide backbone by forming a pair of H-bonds that bridge the γ-turn and stabilize it. Finally, the entire conformer population of Ac-Ala-Gln-NHBn is funneled into a single structure that incorporates the peptide backbone in a type I ß-turn, stabilized by the Gln side chain forming a C7 H-bond to the central amide group in the ß-turn not otherwise involved in a hydrogen bond. This ß-turn backbone structure is nearly identical to that observed in a series of X-(AQ)-Y ß-turns in the protein data bank, demonstrating that the gas-phase structure is robust to perturbations imposed by the crystalline protein environment.