Estimation of the 2.05 helix type i→i hydrogen bond energy at Aib∗-Oxa motif: an isodesmic approach

Bending at the valence angle N–Cα–C′ (τ) is a known control feature for attenuating the stability of the rare intramolecular i→i hydrogen bonded pseudo five-membered ring C5 structures, the so called 2.05 helices, at Aib. The competitive 310-helical structures still predominate over the C5 structures at Aib for most values of τ. However at Aib∗, a mimic of Aib where the carbonyl O of Aib is replaced with an imidate N (in 5,6-dihydro-4H-1,3-oxazine = Oxa), in the peptidomimic Piv-Pro-Aib∗-Oxa (1), the C5i structure is persistent in both crystals and in solution. Here we show that the i→i hydrogen bond energy is a more determinant control for the relative stability of the C5 structure and estimate its value to be 18.5 ± 0.7 kJ/mol at Aib∗ in 1, through the computational isodesmic reaction approach, using two independent sets of theoretical isodesmic reactions.