Date of Award
Fall 2019
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
School
Polymer Science and Engineering
Committee Chair
Sarah Morgan
Committee Chair School
Polymer Science and Engineering
Committee Member 2
Robson Storey
Committee Member 2 School
Polymer Science and Engineering
Committee Member 3
William Jarrett
Committee Member 3 School
Polymer Science and Engineering
Committee Member 4
Vijayaraghavan Rangachari
Committee Member 4 School
Mathematics and Natural Sciences
Committee Member 5
Adam Smith
Committee Member 5 School
Polymer Science and Engineering
Abstract
This dissertation focuses on the development of bio-inspired polymers as models to evaluate binding modes with various proteins through specific design of pendent functionality. Genetic variances can result in abnormal protein behavior in the body, such as aggregation events or mislabeling as an antigen, where polymer/protein complexation can provide insight into protein stability and potential therapeutic approaches. Polymer/protein interactions on the molecular level can occur through various modes, such as hydrogen bonding, electrostatic binding, and hydrophobic interactions. Polymers of different architectures containing acrylamido backbone structures were utilized to study structure/binding interactions in vitro, with the goal of advancing knowledge in the area of therapeutic agent design for disease prevention and control.
The first chapter provides an overview of protein-related disorders, polymers as models/binders, and the physiochemical considerations for polymer/protein complexation. The second chapter utilizes biomimetic glycopolymers containing either glucose- or galactose-pendent groups with stereochemistry matching that of saccharides in the GM1 ganglioside, which is known to exacerbate Aβ aggregation and is implicated in Alzheimer’s disease. The small difference in stereochemistry of the two pendent saccharides results in dramatically different hydrogen bonding patterns for the two glycopolymers, ultimately causing differences in solution conformation and binding characteristics with Aβ peptides. The third chapter discusses the synthesis of low molecular weight anionic polymers for evaluation of non-covalent binding with gliadin (net positive charge at intestinal pH) to determine modes of polymer/protein interactions on the basis of anion strength and hydrophobic character. While electrostatic and hydrophobic interactions result in changes of gliadin’s secondary structure below the isoelectric point, strong electrostatic interactions with sulfonate-containing polymers had the largest impact on gliadin solution behavior. The fourth chapter utilizes surface-functionalized PAMAM dendrimers as synthetic chaperones to prevent or reduce the formation of bovine γ-crystallin aggregates. Successful chaperones displayed the ability to undergo multiple modes of non-covalent interactions with bovine γ-crystallin, resulting in little to no aggregation. The structure/binding interactions for each of these chapters were investigated via a series of biochemical, analytical, and light scattering techniques in vitro.
Copyright
2019, Ashleigh Bristol
Recommended Citation
Bristol, Ashleigh, "Bio-Inspired Polymers as Models for Determination of Non-Covalent Structure/Binding Interactions with Amyloid β Peptides, Gliadin, and Bovine γ-Crystallin" (2019). Dissertations. 1710.
https://aquila.usm.edu/dissertations/1710