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Evolution of Amide Stacking in Larger γ-Peptides: Triamide H-Bonded Cycles

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journal contribution
posted on 01.12.2011, 00:00 authored by William H. James, Evan G. Buchanan, Christian W. Müller, Jacob C. Dean, Dmytro Kosenkov, Lyudmila V. Slipchenko, Li Guo, Andrew G. Reidenbach, Samuel H. Gellman, Timothy S. Zwier
The single-conformation spectroscopy of two model γ-peptides has been studied under jet-cooled conditions in the gas phase. The methyl-capped triamides, Ac-γ2-hPhe-γ2-hAla-NHMe and Ac-γ2-hAla-γ2-hPhe-NHMe, were probed by resonant two-photon ionization (R2PI) and resonant ion-dip infrared (RIDIR) spectroscopies. Four conformers of Ac-γ2-hPhe-γ2-hAla-NHMe and three of Ac-γ2-hAla-γ2-hPhe-NHMe were observed and spectroscopically interrogated. On the basis of comparison with the predictions of density functional theory calculations employing a dispersion-corrected functional (ωB97X-D/6-311++G(d,p)), all seven conformers have been assigned to particular conformational families. The preference for formation of nine-membered rings (C9) observed in a previous study [James, W. H., III et al., J. Am. Chem. Soc. 2009, 131, 14243] of the smaller analog, Ac-γ2-hPhe-NHMe, carries over to these triamides, with four of the seven conformers forming C9/C9 sequential double-ring structures, and one conformer a C9/C14 bifurcated double ring. The remaining two conformers form C7/C7/C14 H-bonded cycles involving all three amide NH groups, unprecedented in other peptides and peptidomimetics. The amide groups in these structures form a H-bonded triangle with the two trimethylene bridges forming loops above and below the molecule’s midsection. The structure is a natural extension of amide stacking, with the two terminal amides blocked from forming the amide tristack by formation of the C14 H-bond. Pair interaction energy decomposition analysis based on the fragment molecular orbital method (FMO-PIEDA) is used to determine the nonbonded contributions to the stabilization of these conformers. Natural bond orbital (NBO) analysis identifies amide stacking with a pair of n → π* interactions between the nitrogen lone pairs and π* orbitals on the carbonyl of the opposing amide groups.