Complementary Strategies for the Design of Protein-like Structure in Unnatural Peptides

Structure and function in proteins are organized according to a hierarchy of increasing levels of complexity. A sequence of L-alpha-amino acids (primary structure) gives rise, by virtue of its amino acid content, to a peptide backbone with domains that have individual propensities to adopt minimal units of structure. These most basic secondary structural units, such as alpha-helices and beta-sheets, further associate intramolecularly (tertiary structure) or intermolecularly (quaternary structure) into the many beautiful and complex structures we observe in nature. The amazing variety of function observed in proteins arises directly from the specific patterning of chemical groups in three dimensions as polypeptides adopt tertiary and quaternary structures. We refer to this progression from amino acid sequence to complex function as the sequence-structure-function paradigm.;This dissertation is organized into two parts, each describing efforts to obtain protein-like structure in unnatural peptide backbones by targeting a different level of the sequence-structure-function paradigm. Chapters 2 and 3 (Part I) relate the discovery a quaternary structural motif that is adopted solely by unnatural peptides composed of alpha-sequence-structure-function paradigm. Chapters 2 and 3 (Part I) relate the discovery a quaternary structural motif that is adopted solely by unnatural peptides composed of alpha- and beta-amino acids in a specific sequence pattern. We describe the preliminary efforts to use this motif as the basis for the first de novo foldamer tertiary structure.;In Part II, the focus switches from the higher-order tertiary and quaternary structure end of the sequence-structure-function paradigm. We move to a step that precedes sequence in this continuum, and investigate the conformational preferences of a new class of unnatural gamma-amino acid building blocks. Chapter 4 reviews the literature concerning the development of foldamers based upon unnatural gamma-amino acids and describes a brief structural analysis of gamma-peptide foldamers that adopt a distinct helical conformation. Chapter 5 describes our efforts to obtain novel, stereochemically pure gamma-amino acids via asymmetric, organocatalytic synthetic methodology. Lastly, in Chapter 6, we relate the structural characterization of peptides containing a novel class of conformationally rigid gamma-amino acids that promote a rare class of secondary structure. Utilizing design strategies from near opposite ends of the sequence-structure-function continuum, we arrive at novel unnatural peptide structures.;Utilizing design strategies from near opposite ends of the sequence-structure-function continuum, we arrive at novel unnatural peptide structures. It is my hope that the work described in this dissertation 1) illustrates the promise of further investigation of the effects of unnatural amino acid substitution into polypeptides with higher order structure and 2) reemphasizes the importance of continuing efforts to investigate novel classes of rigid unnatural amino building blocks. Both approaches can be productive, and the resulting structures are often quite different than what one anticipates.