Early Stages of RNA-Mediated Conversion of Human Prions

Prion diseases are characterized by the conversion of prion proteins from a PrP fold into a disease-causing PrP form that is self-replicating. A possible agent to trigger this conversion is polyadenosine RNA, but both mechanism and pathways of the conversion are poorly understood. Using coarse-grained molecular dynamic simulations we study the time evolution of PrP over 600 μs. We find that both the D178N mutation and interacting with polyadenosine RNA reduce the helicity of the protein and encourage formation of segments with strand-like motifs. We conjecture that these transient β-strands nucleate the conversion of the protein to the scrapie conformation PrP.