Herein, we report on the folding pattern observed in a synthetic peptide featuring two highly mutually dependent, yet strikingly dissimilar, closed networks of hydrogen-bonded rings that work in a cumulative fashion to stabilize the entire folded architecture of the peptide. Structural studies unequivocally suggest that disruption of any one of these mutually-dependent hydrogen-bonded networks is deleterious to the stability of the fully folded conformation of the peptide.
This communication describes the development of conformationally constrained unnatural aromatic amino acids, constructed on rigid backbone wherein the carboxyl and amino groups project in two dimensions (planes) on the aromatic framework. Such a feature offers the possibility of design and development of conformationally ordered synthetic oligomers with intriguing structural architectures distinct from those classically observed. Furthermore, such amino acids will have the potential to extend the conformational space available for foldamer design with diverse backbone conformation and structural architectures.
Strikingly dissimilar hydrogen-bonding patterns have been observed for two sets of closely similar hetero foldamers containing carboxamide and sulfonamides at regular intervals. Although both foldamers maintain conformational ordering, the hydrogen-bonding pattern and backbone helical handedness differ diametrically.
This article details the characteristic conformational features of the Ant‐Pro reverse turn ― a folded pseudo β‐turn motif that displays a closed nine‐membered‐ring hydrogen‐bonded network involving just two amino acid residues, namely anthranilic acid (Ant; a constrained β‐amino acid), and proline (Pro; a constrained α‐amino acid). The results from the extensive investigation of ten crystal structures and their NMR conformations in the solution state provide a clear idea about the conformational characteristics of the Ant‐Pro reverse turn. The Ant and Pro residues, which form the turn segment, maintain a perfect antiperiplanar orientation throughout, leaving little possibility for the formation of the otherwise possible six‐membered hydrogen‐bonding that requires a coplanar disposition of the two amino acid residues, as clearly evident from investigation of several crystal structures. The closed hydrogen‐bonded network observed in the Ant‐Pro reverse turn motif, formed in the forward direction of the sequence (1→2 amino acid interactions) involving only two amino acid residues, is in stark contrast to the native β‐turns that involve four residues to form hydrogen‐bonded network featuring backward 1←4 amino acid interactions. The readily available two‐residue Ant‐Pro motif raises the possibility of a practical utility, particularly in the application of rigidifying flexible peptide backbones by inserting the robust Ant‐Pro reverse turn motifs into their backbone.
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