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

Abstract

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).