Peptides and proteins exist not as single, lowest energy structures, but as ensembles of states separated by small barriers. In order to study these species we must be able to correctly identify their gas phase conformational distributions, and ion mobility spectrometry (IMS) has arisen as an experimental method for assessing the gas phase energetics of flexible peptides. Here, we present a thorough exploration and benchmarking of the low energy conformers of the small, hairpin peptide H+GPGG with the aid of ion mobility spectrometry against a wide swath of density functionals and wave function theory methods. Of the three experimentally-resolved H+GPGG conformers, two possess a cis configuration about the Pro–Gly1 peptide bond while the other adopts a trans configuration. While the trans conformer is disfavored experimentally, CCSD(T)/CBS calculations prefer trans over cis when electronic energies are considered. Only when Gibbs free energies are analyzed does the correct cis/trans preference reveal itself. These results highlight the danger in considering only the electronic energies, which is common practice in electronic structure theory predictions of conformational energy distributions. Dispersion-corrected DFT was also found to be invaluable in the correct prediction of the experimental intensities, with the previously reported combination of uncorrected DFT and electronic energies leading to misleadingly fortuitous error cancellations. Additionally, the effects of temperature and scaling of the frequencies used in obtaining the Gibbs free energies are explored. Finally, the conformational distributions of DPGG, NPGG, EPGG, and QPGG will be reported, where the trans conformer has been found to be heavily disfavored due to intricate hydrogen bonding networks, going against the popular intuition of low-barrier interconversion between these cis/trans species.

Ion mobility-aided, quantum chemical analysis of H+XPGG conformers: The roles of hydrogen bonds, free energies, and dispersion

2019 Spring National Meeting

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