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 et al.'s experimental findings on PrP(138-143) and partially consistent with Jones et al.'s finding on PrP(23-144). We also identify several conformational mismatches when SHa cross-seeds BV and Hu peptides, indicating the existence of a cross-seeding barrier between SHa and the other two sequences. This study sheds light on the molecular mechanism of seed-templating aggregation of prion protein fragments underlying the sequence-dependent transmission barrier in prion diseases.
Keywords: amyloid formation; coarse-grained molecular dynamics; cross-seeding aggregation; fibril elongation; prion protein fragments.
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