The first step in understanding the preferences of flexible peptides, such as beta hairpins, is to be able to correctly assign their gas phase conformational distributions, creating a solid base from which to begin adding on biologically relevant conditions. 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 (28 total functionals) and wave function theory methods (15 WFT methods). The three experimentally resolved IMS peaks were found to correspond to three distinct pairs of conformers, each pair composed of species differing only by the chair or boat configuration of the proline. Two of the H+GPGG conformer pairs possess a cis configuration about the proline alpha carbon–nitrogen bond while the other adopts a trans configuration. While the experimental spectrum reports a higher intensity for the cis-1 conformer than the trans conformer, 13 WFT methods, including a complete basis set CCSD(T) extrapolation, obtain trans to be favored in terms of the zero-point corrected electronic energy. This same effect is seen in the 9 dispersion-corrected density functionals studied, whereas the remaining 19 functionals show more variety. Only when Gibbs free energies are considered do the WFT methods and dispersion-corrected functionals reflect the experimental distribution. CAM-B3LYP-D3BJ emerges as the best-performing density functional, matching the experimental distribution and the CCSD(T)/CBS relative energies within 6%. Further analysis reveals the trans conformer to be favored electronically, but entropically disfavored, leading to the experimental preference of the cis-1 conformer. These results highlight the danger in considering only the electronic energies, which is common practice in electronic structure theory predictions of conformational energy distributions. Additionally, the effects of temperature and scaling of the frequencies used in obtaining the Gibbs free energies are explored.

Electronic energies are not enough: An ion mobility-aided, quantum chemical benchmark analysis of H+GPGG conformers

2019 Spring National Meeting

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