The unique crystallographic signature of a β-turn mimic nucleated by N-methylated phenylalanine and Aib as corner residue: conformational and self-assembly studies

Abstract

The secondary α-amino acid, proline, having high β-turn forming propensity is known to stabilize discrete conformations in peptides. A similar influence is ascribed to N-methylated amino acids with the advantage of the introduction of a side chain functionality. In this report our effort lies to modulate the conformational analysis (solid phase: x-ray diffraction analysis; solution phase: NMR and CD measurements) of two terminally protected synthetic tripeptides Boc-N-MePhe-Aib-Xx-OMe, where Xx is Phe in peptide I and mABA (mABA: meta amino benzoic acid) in peptide II, forming β-turns stabilized by 4 → 1 intramolecular hydrogen bonding. Up to now, a significant amount of work has been dedicated to employing different strategies in stabilizing β-turn mimics. However, to the best of our knowledge, these novel examples represent a unique crystallographic evidence of a β-turn mimic nucleated by an N-methylated amino acid (N-methylated phenylalanine) and Aib as corner residues and stabilized by the conformational features of the acyclic tripeptides. The literature documentation further reveals that the aromatic residue containing the amyloidogenic peptide calcitonin, consists of ribbon like structures, which twist back upon themselves to form a tubular ensemble. Interestingly, the FESEM images of peptide II shows a ribbon like morphology, resulting due to the aggregation of supramolecular helices in higher order self-assembly. Importantly, peptide I which also produces supramolecular helices does not produce any type of morphology under similar conditions emphasizing the importance of the location of the aromatic residue in the peptide sequence in generating a particular morphological structure. This report may open a new avenue in introducing β-turn motifs, replacing proline turns, in the bioactive conformation of selected peptides. They may also assist in understanding the structure and function of misfolded disease causing peptides like prion and Alzheimer's amyloid.