422285 Investigating Seeding and Cross Seeding Fibrillation of Prion Protein Fragments Using Discontinuous Molecular Dynamics

Thursday, November 12, 2015: 8:30 AM
255B (Salt Palace Convention Center)
Yiming Wang, Chemical and Biomolecular Engineering Department, North Carolina State University, Raleigh, NC and Carol K. Hall, Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC

Transmissible spongiform encephalopathies are associated with the misfolding and aggregation of normal cellular prion protein into β-sheet-rich amyloid fibrils. Seeding-induced aggregation of these proteins is believed to be a major cause of these diseases. The infectious agents called prions are transmissible even between different species by cross-seeding of amyloid fibrils, which leads to new prion strains. Strong evidence indicates that human may develop a variant form of Creutzfeldt-Jakob disease by consuming cattle products contaminated with the agent of Bovine spongiform encephalopathy. In this work, we investigated the effect of species-specific mutations on seeding and cross-seeding fibrillation of the prion protein fragments (PrP128-141 and PrP120-144) from three species (human, mouse and Syrian hamster) using discontinuous molecular dynamics simulation. Preliminary results show that point mutations (isoleucine to methionine at positions 138 and 139) reduce the tendency of prion protein fragments to form fibrils. In seeded fibrillation simulations, pre-formed fibrils accelerate the aggregation process by a seeding-induced mechanism. Also, our cross seeding simulations indicate that the preformed fibril determines the structure of the elongated fibril regardless of the point mutation in the protein primary structure. Our results provide molecular-level insights into the effect of point mutations on seeding and cross-seeding fibrillation of prion protein.

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See more of this Session: Thermophysical Properties of Biological Systems
See more of this Group/Topical: Engineering Sciences and Fundamentals