Unusual Folding Propensity of an Unsubstituted ,-Hybrid Model Peptide: Importance of the CHO Intramolecular Hydrogen Bond

The single-crystal X-ray diffraction analysis of a ,-hybrid model peptide Boc--Ala--Abu-NH2 revealed the existence of four crystallographically independent molecules (A, B, C and D conformers) in the asymmetric unit. The analysis revealed that unusual -turn-like folded structures predominate, wherein the conformational space of non-proteinogenic -Ala and -Abu residues are restricted to gauche-gauche-skew and skew-gauche-trans-skew orientations, respectively. Interestingly, the U-shaped conformers are seemingly stabilised by an effective unconventional CHO intramolecular hydrogen bond, encompassing a non-covalent 14-membered ring-motif. Taking into account the signs of torsion angles, these conformers could be grouped into two distinct categories, A/B and C/D, establishing the incidence of non-superimposable stereogeometrical features across a non-chiral one-component peptide model system, that is, mirror-image-like relationships. The natural occurrence of -Ala and -Abu entities in various pharmacologically important molecules, coupled with their biocompatibilities, highlight how the non-functionalised ,-hybrid segment may offer unique advantages for introducing and/or manipulating a wide spectrum of biologically relevant hydrogen bonded secondary structural mimics in short synthetic peptides.