The UTC Graduate School is pleased to announce that Masumi Sugiyama will present Doctoral research titled, Topology of Neurodegenerative Diseases on 06/20/2024 at 11:00AM in Zoom https://tennessee.zoom.us/j/82221283270?from=addon . Everyone is invited to attend.
Computational Science
Chair: Chris Cox
Co-Chair:
Abstract:
New topological and geometrical methods in knot theory enable the rigorous measurement of entanglement of open curves in 3-space for the first time. These 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 involved in a class of neurodegenerative diseases, called tauopathies. By employing topological measures (linking number, writhe and second Vassiliev measure) on crystal structures of tau filaments available in the Protein Data Bank, this research has enabled a new classification of tauopathies based on the handedness of their global conformations and the handedness of the relative orientations of their repeats which mainly comprise the cores of tau folds. These tools also enable identifying important sites in those filaments, such as the PGGG motifs, as well as the known to promote aggregation 301 mutation site. Additionally, tau antibody analysis shows the mathematical topology of an antibody can predict antigen binding sites for screening for therapeutics. The dissertation is organized as follows: Chapter 1 provides the background of knot theory and its applications as well as the introduction of tau filament structures and functions. In Chapter 2 we cover the definitions and mathematical properties of topological tools used in this dissertation. Chapter 3 presents classifications of tauopathies based on global and local structures of different tauopathy filaments. Next, in Chapter 4, we use topology as a predictor of important sites in tau filaments. Chapter 5 describes coarse grained molecular dynamics simulations of unfolded tau proteins in equilibrium and non-equilibrium conditions that reveal aspects of the topological landscape of tauopathies. Finally, the conclusions of this dissertation are summarized in Chapter 6.