Ph.D defense: Rate Kinetics and Molecular Dynamics of the Structural Transitions in Amyloidogenic Pr

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Venue:CP 220

by Timothy Steckmann, adviser Dr. B. Gerstman

Amyloid fibril aggregation is associated with several horrific diseases such as Alzheimer’s, Creutzfeld-Jacob, diabetes, Parkinson’s and others. This dissertation explores how hydrogen bonds break and form and the heterogeneity of amyloid-forming systems.

Amyloid fibrils are composed of proteins that originate in innocuous structure. On the basis of experimental data, I have developed a mathematical model for the population kinetics of the reaction pathways and determined rate parameters for protein structural conversion and aggregation during the entire fibrillogenesis process, including the molecular species that accelerate the conversions. To better understand the molecular basis of the protein structural transitions and aggregation, I report on molecular dynamics (MD) computational studies on the formation of amyloid protofibrillar structures in the small model protein ccβ, which undergoes many of the structural transitions of the larger, naturally occurring amyloid forming proteins. Two different structural transition processes involving hydrogen bonds are observed for aggregation into fibrils: the breaking of intrachain hydrogen bonds to allow β-hairpin proteins to straighten, and the subsequent formation of interchain hydrogen bonds during aggregation into amyloid fibrils. Both the mathematical modeling of the population kinetics and the MD simulations show that molecular structural heterogeneity is a major factor in the process. The MD simulations also show that intrachain and interchain hydrogen bonds breaking and forming is strongly correlated to the process of amyloid formation.