Identifying Intermediate States in Prion Protein Folding Pathway: A Possible Precursor to the Misfolded State?

Aggregation of prion proteins causes neurodegenerative disorders. The misfolded form of monomeric cellular prion protein leads to toxic protein aggregates rich in β-sheets. Pathological scrapie form of prion protein also catalyzes the conversion of cellular protein to the infectious conformation. Therefore it is very important to understand the mechanism of structural transition of a prion protein from a cellular functional form to the scrapie form. To probe the structures of transient intermediates populated in the folding pathways of prion protein, which can be probable precursors to the pathological misfolded forms, we performed molecular dynamics simulations to probe the folding pathways of prion protein using coarse-grained protein models. The protein populates an intermediate, which is globular and resembles a molten globule like structure where only the β 1 strand detaches from the rest of the folded protein structure. This observation also supports the NMR studies, which report the partial unfolding of the β 1 strand. This conformation might possibly be a precursor to the misfolded or the scrapie prion form