Long-Time Scale Fluctuations of Human Prion Protein Determined by Restrained MD Simulations

Cellular prion protein (PrP^C) has the ability to trigger transmissible lethal diseases after in vivo maturation into a toxic amyloidogenic misfolded form (PrP^Sc). Here, we use hydrogen exchange protection factors in restrained molecular dynamics simulations to characterize long-time scale fluctuations in human PrP^C. We find that the regions of residues 138–141 and 183–192 form new β-strands in several exchange-competent structures. Moreover, these structural changes are associated with the disruption of native contacts that when tethered prevent fibril formation. Our findings illustrate the structural plasticity of PrP^C and are valuable for understanding the conversion of PrP^C to PrP^Sc.