Committee Chair

Panagiotou, Eleni

Committee Member

Skjellum, Anthony; Cox, Christopher L. (Christopher Lee); Wang, Jin

Department

Dept. of Computational Science

College

College of Engineering and Computer Science

Publisher

University of Tennessee at Chattanooga

Place of Publication

Chattanooga (Tenn.)

Abstract

New topological and geometrical methods in knot theory provide a way to rigorously measure the entanglement of open curves in 3-space for the first time. These methods enable the topological analysis of physical systems of filaments, such as those formed by proteins. In this dissertation we employ tools from knot theory in combination with available experimental data and molecular simulations to analyze the topological complexity of tau proteins. These proteins are involved in a class of neurodegenerative diseases, called tauopathies. The methods developed in this dissertation are general and applicable to other proteins as well as any physical systems of filaments. By using topological measures (Linking Number, Writhe and second Vassiliev measure) to quantify three-dimensional structures of tau filaments in the Protein Data Bank, this research provides a new classification of tauopathies based on the global and local structures of different tau filaments. This novel classification reveals more subtle differences in the structures of diseases with different pathologies that were previously unknown. Moreover, these tools also predict important sites in tau filaments such as the PGGG motifs that stabilize those filaments, as well as the 301 mutation site known experimentally to promote aggregation. The novelty and importance of these results is that they are based solely on static structures of proteins, yet they seemingly predict aspects of protein folding and aggregation. This points to these methods as tools to predict novel structure- and site-specific therapeutics. Indeed, tau antibody analysis shows the mathematical topology of an antibody can predict antigen binding sites. By employing coarse grained molecular dynamics simulations of full-length tau proteins in solution, we find that co-factors such as RNA and stress can affect the topology/geometry of unfolded tau proteins. Moreover, it is shown that local conformations of tau proteins with these co-factors are more favorable than those of tau filaments alone, which may imply that they could stabilize the proteins. The data also demonstrate that knotting of a tau protein in the unfolded ensemble is a possible but rare event.

Acknowledgments

This endeavor would not have been possible without the support and guidance of individuals who contributed and extended their valuable assistance throughout the course of my PhD degree. I would like to express my deepest gratitude to my supervisor, Dr. Eleni Panagiotou, for her invaluable advice, continuous support and immense expertise that carried me through all the phases of conducting research and writing my dissertation. My sincere gratitude extends to my dissertation committee members, Dr. Anthony Skjellum, Dr. Christopher Cox and Dr. Jin Wang for their generous support and guidance which enabled the continuation of my PhD study and have impacted very positively on my professional as well as personal growth. I am extremely grateful to my partner who has supported me all the way through my academic journey. His tremendous understanding and encouragement, even when things were overwhelming, made this achievement possible. I would also like to acknowledge the support from the National Science Foundation (OAC-2201497 and DMS-1913180), the mathematics Department and the Research Institute at the University of Tennessee at Chattanooga during my PhD study.

Degree

Ph. D.; A dissertation submitted to the faculty of the University of Tennessee at Chattanooga in partial fulfillment of the requirements of the degree of Doctor of Philosophy.

Date

8-2024

Subject

Knot theory; Proteins--Conformation; Proteins--Structure; Nervous system--Degeneration

Keyword

Knot theory; topology; geometry; protein structures; Tauopathies; Molecular dynamics simulation

Document Type

Doctoral dissertations

DCMI Type

Text

Extent

xv, 79 leaves

Language

English

Rights

http://rightsstatements.org/vocab/InC/1.0/

License

http://creativecommons.org/licenses/by/4.0/

Date Available

2-1-2025

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Available for download on Saturday, February 01, 2025

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