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Dissertation/Thesis Abstract

Using α-helices with dynamic constraints to probe peptide folding and protein-protein interactions
by Miller, Stephen E., Ph.D., New York University, 2014, 242; 3665182
Abstract (Summary)

Proteins typically adopt defined structural conformations when interacting with other biomolecules. The ability to predictably control the three-dimensional structure of proteins and peptides can have wide-ranging implications. This thesis describes efforts to control the conformation of peptides with reversible linkages based on the hydrogen bond surrogate (HBS) approach for stabilizing α-helices. Reversible helices are then used as probes to study protein folding and as ligands for protein-protein interactions (PPIs).

Chapter 1 introduces the relationship between protein structure, folding, and function. Some key methods for controlling peptide and protein conformation are described, with a focus on synthetic strategies that allow reversible control over structure.

Chapter 2 describes a new reversible α-helix scaffold, based on the HBS strategy, that utilizes a disulfide constraint (dsHBS). The approach allows for the conformation of a peptide to be precisely controlled through the oxidation of bis-thiol compounds and the subsequent reduction of the dsHBS.

Chapter 3 investigates the effects N-terminal point mutations have on the rate of α-helix nucleation using dsHBS peptides. Helix nucleation is often neglected in studies examining helix-coil transition theory. The results from experimental and computational studies suggest that the effects of side chain residues in helix nucleation differ from helix propagation.

Chapter 4 examines the use of dsHBS peptides as biological probes. The p53-MDM2 interaction is chosen as a model PPI for investigating the binding of intrinsically disordered proteins and for the development of screening methods that can identify helical peptide inhibitors from small libraries.

Chapter 5 describes the design and attempted synthesis of an HBS derivative constrained by a strong ionic interaction (iHBS), rather than a covalent linkage. Since salt bridges buried within the hydrophobic interior of proteins can impart significant structural stability, it is proposed that an iHBS peptide could favor helix formation by shielding the backbone salt bridge from solvent. However, intermediate compounds were unstable and significant redesigning of the project is necessary for continued studies involving iHBS.

Indexing (document details)
Advisor: Arora, Paramjit S.
Commitee: Canary, James W., Kallenbach, Neville R., Weck, Marcus
School: New York University
Department: Chemistry
School Location: United States -- New York
Source: DAI-B 76/04(E), Dissertation Abstracts International
Subjects: Organic chemistry, Biophysics
Keywords: Constrained peptides, Helix mimetics, Helix nucleation, Hydrogen bond surrogate, Protein-protein interaction, Reversible helix
Publication Number: 3665182
ISBN: 978-1-321-37485-8
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