Santhouse, Jacqueline
(2022)
Effects of Backbone Modification on Proteomimetics.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The extensive functionality of proteins has given rise to myriad scientific disciplines, including use of covalent modifications to change and probe structure and function. At their base, proteins are a linear sequence of L-α-amino acids in a repeating backbone displaying canonical sidechains. Simple backbone modifications affect the structure and properties of proteins in ways that are not yet fully understood, and that gap in knowledge restricts their design and application. In this dissertation, I document efforts toward understanding chemical backbone modification effects on structure and folding thermodynamics and kinetics of proteins.
Design principles for heterogeneous-backbones have guided creation of protein mimics, but their scope and limitations remain undefined. While a large body of work explores various backbone modifications in secondary and stable tertiary structure, there is little on energetically delicate systems. Implementation of these principles in modestly stable folds reveals their tolerance for modifications with stability consequences.
Individual modification types have been explored in isolated secondary structures to understand their effects on protein properties, yet the complexity of tertiary structure introduces several questions. Work described within tests backbone modifications in a tertiary fold, noting differences in folding thermodynamics due to modification type and location. This work finds that both the type and location hold significant importance to the effects observed, suggesting that current design principles require more consideration of the tertiary fold.
Additional work on this series explores the effects on folding kinetics, further highlighting an importance in the location of modification. Folding rate changes differ by orders of magnitude based on only modification location. Thus, this work shows the importance of understanding the folding mechanism in designing heterogeneous-backbone tertiary structures.
The applicability of heterogeneous-backbones in protein mimics relies on the quality of design principles. To utilize these backbones, in depth understanding of their effects and limitations is required. Thus, I have explored the limitations of common backbone modifications and furthered understanding of the effects of individual modification types. The systematic analysis of individual monomer types has not yet been done, and the analysis of effects on folding kinetics in a tertiary fold is the first of its kind.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
13 August 2022 |
| Date Type: |
Publication |
| Defense Date: |
15 April 2022 |
| Approval Date: |
19 December 2024 |
| Submission Date: |
25 August 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
176 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Proteomimetics |
| Date Deposited: |
20 Dec 2024 01:12 |
| Last Modified: |
20 Dec 2024 13:45 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43658 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}