Comparison of the unfolding and oligomerization of human prion protein under acidic and neutral environments by molecular dynamics simulations

Highlights: • The work investigated the stability of PrP^C by combining coarse-grained model and all-atom molecular simulations in the two different environments and shedded light on the mechanism of misfolding and oligomerization during the conversion of PrP^C to PrP^Sc. • The results show that the unfolding of PrP^C starts from the opening of the folded domain with α1 moving away from α2α3 domain, and then arrives at a metastable intermediate, and forms a more stable dimer complex in the end. • This work can unravel the mechanism of the early stage of conformational conversion and dimerization of prion protein in the acidic environment, and provide significant hints for the development of anti-prion therapeutics. Aggregation of the misfolded scrapie prion protein (PrP^Sc) is known to cause neurodegenerative diseases. In this paper, we have investigated the stability of PrP^C by combining coarse-grained model and all-atom molecular simulations. Our results show that the unfolding of PrP^C starts from the opening of the folded domain with α1 moving away from α2α3 domain, and then arrives at a metastable intermediate, and forms a more stable dimer complex in the end. This work unravels the mechanism of the early stage of conformational conversion and dimerization of prion protein and provides significant hints for the development of anti-prion therapeutics.