Prion diseases are infectious neurodegenerative diseases that are capable of cross‐species transmission, thus arousing public health concerns. Seed‐templating propagation of prion protein is believed to underlie prion cross‐species transmission pathology. Understanding the molecular fundamentals of prion propagation is key to unravelling the pathology of prion diseases. In this study, we use coarse‐grained molecular dynamics to investigate the seeding and cross‐seeding aggregation of three prion protein fragments PrP(120–144) originating from human (Hu), bank vole (BV), and Syrian hamster (SHa). We find that the seed accelerates the aggregation of the monomer peptides by eliminating the lag phase. The monomer aggregation kinetics are mainly determined by the structure of the seed. The stronger the hydrophobic residues on the seed associate with each other, the higher the probability that the seed recruits monomer peptides to its surface/interface. For cross‐seeding aggregation, we show that Hu has a strong tendency to adopt the conformation of the BV seed and vice versa; the Hu and BV monomers have a weak tendency to adopt the conformation of the SHa seed. These two findings are consistent with Apostol
This content will become publicly available on January 5, 2025
The Prion protein is the molecular hallmark of the incurable prion diseases affecting mammals, including humans. The protein-only hypothesis states that the misfolding, accumulation, and deposition of the Prion protein play a critical role in toxicity. The cellular Prion protein (PrPC) anchors to the extracellular leaflet of the plasma membrane and prefers cholesterol- and sphingomyelin-rich membrane domains. Conformational Prion protein conversion into the pathological isoform happens on the cell surface.
- Award ID(s):
- 2320718
- PAR ID:
- 10536896
- Publisher / Repository:
- Frontiers
- Date Published:
- Journal Name:
- Frontiers in Bioinformatics
- Volume:
- 3
- ISSN:
- 2673-7647
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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