Early Stages of RNA-Mediated Conversion of Human Prions

Abstract

Prion diseases are characterized by the conversion of prion proteins from a PrP C fold into a disease-causing PrP SC 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 C 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 SC .