(231e) Molecular Insights into the Surface Catalyzed Secondary Nucleation of Amyloid-?40 (A?40) By the Peptide Fragment A?16-22
- Conference: AIChE Annual Meeting
- Year: 2019
- Proceeding: 2019 AIChE Annual Meeting
- Group: Engineering Sciences and Fundamentals
- Time: Monday, November 11, 2019 - 4:30pm-4:45pm
The misfolding and aggregation of amyloid-Î² (AÎ²) proteins in mammalian brains, and the subsequent formation of amyloid plaques, plays a central role in a number of fatal neurodegenerative diseases, including Alzheimerâs 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 AÎ²(1-40) and AÎ²(16-22) peptides, two widely studied peptide fragments of Alzheimerâs peptide, AÎ²(1-42). Here, we analyze the co-aggregation of AÎ²(1-40) and AÎ²(16-22) peptides using both simulation and experimental techniques. We demonstrate that AÎ²(16-22) increases the aggregation rate of AÎ²(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 AÎ²(1-40) monomers/oligomers on the surface of pre-formed AÎ²(16-22) fibrils nucleate AÎ²(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.