En route towards the peptide gamma-helix: X-ray diffraction analyses and conformational energy calculations of Adm-rich short peptides

We performed the solution-phase synthesis of a set of model peptides, including homo-oligomers, based on the 2-aminoadamantane-2-carboxylic acid (Adm) residue, an extremely bulky, highly lipophilic, tricyclic, achiral, C-alpha-tetrasubstituted alpha-amino acid. In particular, for the difficult peptide coupling reaction between two Adm residues, we took advantage of the Meldal's alpha-azidoacyl chloride approach. Most of the synthesized Adm peptides were characterized by single-crystal X-ray diffraction analyses. The results indicate a significant propensity for the Adm residue to adopt gamma-turn and gamma-turn-like conformations. Interestingly, we found that a -CO-(Adm)2-NH- sequence is folded in the crystal state into a regular, incipient gamma-helix, at variance with the behavior of all of the homo-dipeptides from C-alpha-tetrasubstituted alpha-amino acids already investigated, which tend to adopt either the beta-turn or the fully extended conformation. Our density functional theory conformational energy calculations on the terminally blocked homo-peptides (n = 2-8) fully confirmed the crystal-state data, strongly supporting the view that this rigid C-alpha-tetrasubstituted alpha-amino acid residue is largely the most effective building block for gamma-helix induction, although to a limited length (anti-cooperative effect).