Nature relies on oligomers and polymers with compact and specific folding patterns (peptides, proteins, and RNA) to carry out sophisticated tasks like catalysis and signal transduction. This reliance suggests that unnatural oligomers and polymers with well-defined folding propensities would provide useful starting points for generating biomimetic activities or for creating new types of chemical activities. We are exploring this very broad hypothesis in the context of b-amino acid oligomers (beta-peptides). Considerable progress in this new area has been made over the past three years, ands we propose here to expand our study of beta-peptide folding preferences and to create beta-peptides with useful biological activities. The proposed research has three specific aims. (1) We will continue to explore the relationship between primary structure and secondary structure in beta-peptides. We are particularly interested in strategies that provide stable secondary structures in aqueous solution with a relatively small number of beta-amino acid residues. Elucidating the origins of beta-peptide secondary structure specificity will promote the use of beta-peptides for biomedical applications. (2) We will link amphiphilic beta-peptide secondary structural elements to create tertiary structures. This goal has great fundamental importance since there is presently no example of an unnatural oligomer or polymer that fold to a specific tertiary structure. (3) We propose that well-folded beta-peptides will be able to mimic the functions of natural peptides and proteins that must adopt specific secondary or tertiary structures for activity. We will test this hypothesis by trying to create beta-peptide mimics of natural antimicrobial peptides and beta-peptide antagonists of specific protein-protein interactions.
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