Unraveling the aggregation dynamics of amyloidogenesis: A data-driven mathematical modeling approach

Abstract

Proteins often get misfolded into highly ordered amyloid aggregates that are found to be associated with various neurodegenerative diseases. However, the dynamical events that lead to such self organization of different types of proteins are still poorly understood due to the experimentally untractable complex molecular mechanism, which governs the process of amyloidogenesis. Herein, we propose a generic and data-driven mathematical modeling approach that enables us to decipher a most probable molecular mechanism responsible for amyloidogensis in a context dependent manner. The preferred model efficiently elucidates various aspects of amyloid forming kinetics as a function of initial protein concentration, and qualitatively predicts the dynamics of amyloidogenesis for point mutated proteins. Importantly, the model analysis reveals that intermediate aggregates formed just after the primary necleation steps plays a vital role in dictating the nature of amyloid forming kinetics. Moreover, our model makes experimentally feasible insightful predictions to formulate better therapeutic measures in future to counter unwanted amyloidogenesis by just fine-tuning the molecular interactions related to amyloidogenesis. Author SummaryIn cells, proteins mostly function by being in a native folded conformation. However, under certain circumstances, some of these proteins undergo high degree of aggregation and eventually misfold to form highly stable amyloid aggregates that are often involved in different neurodegenerative disease progression and pathogenesis. To develop appropriate therapeutic strategies to resist such oligomerazation of protein, it is imperative to unravel the molecular interactions that essentially organize the dynamical events of amyloidogenesis. We have proposed a generic computational modeling framework to elucidate the important molecular events that govern the dynamics of amyloid formation. Our model reconciles diverse set of experimental observations including different mutant phenotyes from a dynamical perspective, and predicts possible ways to control the kinetics of amyloid formation experimentally. In future, these insights will be helpful to design drugs to treat patients with neurodegenerative disorders. Importantly, our model, in general, will be quite useful to figure out the important molecular events that are orchestrating the amyloidogenesis of different amyloid forming proteins.