Determination of Nucleation Mass for Amyloid-β Aggregation

Abstract

Protein misfolding and concomitant self-assembly towards ordered aggregates (amyloids) has emerged as an important event governing both functional and pathological events in cells. Both structurally and biophyiscally, amyloid formation is highly conserved involving the conversion of proteins (intrinsically disordered or globular) from their native monomeric states to well-organized, fibrillar aggregates in a nucleation-dependent manner. Although a plethora of literature exists on modeling such aggregations, the molecular mechanisms are poorly understood, especially those leading up to nucleation. In our study we use Aβ as the model system to test our theoretical framework for amyloid aggregation. Specifically, we focus on nucleation, which we believe to be a critical gate-keeping event which controls the dynamics of the entire pathway and determines the physiochemical and biochemical fate of the aggregates formed. In this study we clarify the mechanics of aggregation leading to nucleation, and how fibril morphology depends on size and conformation of the nucleus. The pre-nucleation dynamics are modeled by ODE simulations based upon mass action kinetics and also supported by experimental data. An alternative, novel approach, based upon stability of the equilibria is utilized to identify the optimal nucleation mass range and properties associated with the nucleus.