Foldamers: Design, synthesis, and characterization of non-natural peptides with diverse backbones

The protein-folding problem has greatly advanced over several decades, and our understanding of protein folding since Lenivthal\u27s paradox and the folding funnel concept has immensely expanded. New findings have created a limitless number of research opportunities that have lead to more solutions to the protein-folding problem. While the fundamental principals guiding the protein-folding problem have been established there remain some unsolved challenges. Exactly how proteins fold is not well understood and remains a fundamental question in biochemistry. By elucidating mechanisms of protein folding, unfolding, and stabilization, we gain significant insight into links between folding dynamics and the origins of disease, and lay groundworks for the design of new materials. Synthetic foldamers, designed to mimic proteins, offer great stabilities and protease resistance and thus, are excellent model systems for examining effects of backbone flexibility on the dynamics of protein folding and protein-protein interactions. This thesis focuses on two aspects of foldamers: folding and unfolding kinetics and biological applications. The study of the folding-unfolding kinetics of secondary and quaternary 14-helical β-peptide foldamers aims to understand how the additional degree of freedom and increased backbone flexibility affect folding dynamics and to benchmark folding rates of β-peptides. The T-jump induced relaxation kinetics of a secondary β-peptide occurs in nanoseconds and is noticeably slower than alanine-based α-helical peptides. The T-jump kinetics of the quaternary foldamer occurs on an even slower time scale (minutes). These differences appear to indicate that folding energy landscapes of these β-peptides and their α-helical counterparts are notably distinct. The biological relevance of synthetic foldamers was studied on a second class of foldamers that self-assemble, recognize and antagonize the antithrombotic action of heparin. The association state of salicylamide-α-amino acid foldamers depends on their interaction with heparin. Analytical ultracentrifugation, UV-visible absorption, circular dichroism spectroscopy, and isothermal calorimetry were utilized to demonstrate their association. The stable and active associated form of these foldamers occur in the presence of fondaparinux, a synthetic pentasaccharide heparin analog; in the absence of fondaparinux the foldamer favors a monomer, which can be rapidly cleared