Undergraduate Florida Institute of Technology Palm Bay, Florida, United States
Yasmine Sobhi (Florida Institute of Technology)| Shaohua Xu (Florida Institute of Technology)
Protein aggregation and amyloid fiber formation are early events in a plethora of human diseases, including neurodegenerative diseases like Alzheimer's disease (AD). Currently, the mechanism for the formation of amyloid fibers is not entirely understood. The general belief is that fiber formation results from protein misfolding, where the conversion of proteins to abnormal structures, like β-sheets, results in aggregation. However, atomic force microscopy data suggest that aggregation occurs in two steps: formation of colloids, known as nucleation units, and aggregation of said units to form fibers. We apply DLVO theory to elucidate Aβ1-42 aggregation, the formation of colloids or oligomers, and the linear aggregation of the latter to fibers. Specifically, we investigate (1) what restricts the size of the colloids and (2) what drives the linear aggregation of the colloids. We propose that as Aβ1-42 monomers aggregate, the charge of the colloid becomes overwhelmingly large, and attractive forces can no longer overcome repulsive forces, thereby limiting the size of the colloid. A cross α-sheet structure is also speculated to be generated during the initial aggregation process, yielding colloids with a strong dipole. Charge-dipole interaction is also thought to drive linear colloidal aggregation. Our result shows that as the Aβ1-42 monomers aggregate to form colloids, overall charge of the unit increases, eventually repelling approaching monomers and preventing colloids from growing further in size, with the charge of the colloid being 3.36×10-17 C at a radius of 5 nm. Charge-dipole interactions were found to increase with the size of the colloids, eventually driving linear colloidal aggregation. The fiber's axis is perpendicular to the colloid's dipole moment, and the chain eventually assumes a thermodynamically stable cross β-sheet structure. We conclude that increased charge of the colloid, as additional monomers are added, acts as the limiting factor restricting the size of the colloids. A transition from a cross α-sheet to a cross β-sheet structure was essential for the proposed linear colloidal aggregation model.