Dissertation/Thesis Abstract

Further Expansions of Functionality in Beta-Peptide Bundles
by Miller, Jonathan, Ph.D., Yale University, 2015, 158; 3663651
Abstract (Summary)

The function of natural macromolecules is inextricably linked to their structure. The study of these molecules has resulted in a blossoming understanding and control of this relationship, but it has also highlighted the relative paucity of natural forms. Chemical biology has used the structural lessons learned from natural polymers to endow a variety of unnatural macromolecules with structure. Collectively, these molecular families are called "foldamers." While the variety of structures available to foldamer scaffolds has grown tremendously in the past decade, endowing these assemblies with function has been possible only intermittently, and only for certain classes of function. This dissertation describes efforts to expand the functional scope of β-peptides, a foldamer comprised of β-amino acids, by enabling metal binding and catalytic activity in their assemblies.

Part I describes the development of a Cd(II)-binding β-peptide bundle. First, it describes an exploration of the chemistry of β3-homocysteine in the context of a β-peptide scaffold, and describes a hitherto undocumented self-cleaving reaction undergone by this residue. Then, it describes the rational design, the synthesis, and the characterization of Zwit YK-C, the aforementioned metal-binding bundle. This β-peptide folds cooperatively into an octameric bundle, like the peptide on which it is based, and binds two Cd(II) ions in a distinct bi-coordinate array. The metal-binding activity stabilizes the quaternary structure of the bundle as judged by its thermal stability. Furthermore, the affinity of the bundle for its Cd(II) ligand is shown exhibit allosteric cooperativity: another heretofore undocumented quality of foldamer activity.

Part II describes the development of a β-peptide bundle capable of catalyzing the aldol reaction in homogeneous aqueous solution. First, it describes the development of a ketone-bearing β-amino acid for use with a modular β-peptide modification system using the oxime-forming reaction. Then, it describes the development of two hydroxylamineproline prosthetics that are incorporated into a β-peptide bundle. The peptide-proline oximes are characterized, and display catalytic activity modestly superior to that of a widely-used small molecule catalyst also based on praline.

Overall, these two achievements represent a significant extension of the functional remit of β-peptide bundles. Using the tools described herein, it is likely possible to develop further bundles with a wide variety of metal ligands and catalytic activites.

Indexing (document details)
Advisor: Schepartz, Alanna
Commitee:
School: Yale University
School Location: United States -- Connecticut
Source: DAI-B 76/11(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Biochemistry, Organic chemistry
Keywords: Asymmetric catalysis, Beta peptide, Chemical biology, Foldamer, Metal binding
Publication Number: 3663651
ISBN: 9781321957594
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