(231e) Molecular Insights into the Surface Catalyzed Secondary Nucleation of Amyloid-?40 (A?40) By the Peptide Fragment A?16-22

The misfolding and aggregation of amyloid-β (Aβ) proteins in mammalian brains, and the subsequent formation of amyloid plaques, plays a central role in a number of fatal neurodegenerative diseases, including Alzheimer’s Disease. Fundamental understanding of protein misfolding and aggregation has thus become an active research topic as it is crucial for elucidating disease pathology and could help guide the development of potential therapeutics. In our work, we apply discontinuous molecular dynamics (DMD) simulation combined with an intermediate resolution protein model, PRIME20, to understand the thermodynamics and kinetics underlying the aggregation of Aβ(1-40) and Aβ(16-22) peptides, two widely studied peptide fragments of Alzheimer’s peptide, Aβ(1-42). Here, we analyze the co-aggregation of Aβ(1-40) and Aβ(16-22) peptides using both simulation and experimental techniques. We demonstrate that Aβ(16-22) increases the aggregation rate of Aβ(1-40) through a surface catalyzed secondary nucleation mechanism. Discontinuous molecular dynamic (DMD) simulations allows the aggregation to be tracked from the initial random coil monomer to the catalysis of monomer nucleation on the fibril surface. Taken together, the results provide insight into how dynamic interactions between Aβ(1-40) monomers/oligomers on the surface of pre-formed Aβ(16-22) fibrils nucleate Aβ(1-40) amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly.