Construction of Ordered Self-Assembled Architectures from Peptide Foldamers Composed of Non-natural Amino Acids

Abstract

Inspired by the functions of proteins and metalloproteins, extensive efforts have been made over the years to mimic their structures and functions using non-natural amino acid building blocks. The folded structures derived from the oligomers of beta, gamma, and delta amino acids and their mixed sequences along with alpha-amino acids offer a wide range of structural diversity with potential applications in biology and materials. In our previous studies, we have shown the remarkable beta-double helical structures from the homo-oligomers of 4,4-dimethyl substituted (E)-vinylogous amino acids and stable helical structures from short sequences of alpha, gamma-hybrid peptides. However, understanding the requirement of amino acid residues and peptide sequences to form a double helical structure was an illusion. In the present study, we have revealed that the beta-double helical structures not confined to the oligomers 4,4-dimethyl substituted (E)-vinylogous amino acids, even the mixed sequences composed of 3,3-dimethyl substituted gamma-amino acid (Adb) along with 4,4-dimethyl substituted (E)- vinylogous amino acids and also form artificial beta double-helical structures. In sharp contrast, replacing 3,3-dimethyl gamma-amino acids with 4,4-dimethyl gamma-amino acids also leads to double helical structures. The structural analysis of the double helix shows achiral in nature. Furthermore, we have examined the transformation of the achiral nature of the beta-double helices into chiral double helices by attaching chiral amines at the C-terminal of the peptides. Both single crystal structure and solution state analysis reveal that even after attaching a chiral amine, the peptide maintained its double helical nature, and chirality is induced throughout the peptide sequences. In contrast to the double helical structures, the alpha-gamma-alpha-hybrid tripeptides composed of saturated gamma-amino acids gave stable helical structures in single crystals and solution state. We have examined these stable helical structures in the construction of various types of metal-coordinated ordered supramolecular architectures. We have used Ag+ , Cu2+ , Zn2+ , and Cd2+ ions to understand the helical structure organization in the presence of metal ions. The stable caged porous networks obtained in the presence of ZnCl2 have been further explored as hosts to encapsulate guest solvent molecules. On the other hand, the structural analysis of CdI2-coordinated peptide reveals entirely different, remarkable left-handed superhelical architectures. Instructively, the hybrid tripeptide with valine residues forms metallogels in the presence of Ag+ and Cu2+ ions. The X-ray analysis of single crystals obtained from the gel matrix reveals that the helical structure is maintained during the self-assembly process. Overall, the sterically constrained chiral and achiral gamma-amino acids can be used xvi to construct different types of peptide foldamers. These secondary structure mimetics can be used to construct remarkably ordered supramolecular assemblies. The work presented here opens a new window to further explore these short helices and beta-double helices as new tools for the design of peptide-based biomaterials.