The prion protein globular domain and disease-related mutants studied by molecular dynamics simulations.

Abstract

In humans, familial forms of transmissible spongiform encephalopathies (TSE; "prion diseases") have been shown to segregate with the exchange of individual amino acids in the prion protein (PrP) sequence. We used the NMR structure of the globular domain of mouse PrP in the cellular form (PrP(C)) as a starting point for investigations by long-time molecular dynamics (MD) simulations at ambient temperature of likely impacts of such mutations on the PrP(C) structure, making use of the fact that species-related amino acid replacements between mouse PrP and human PrP are spatially well separated from the disease-related mutations in human PrP. In the MD simulations these amino acid substitutions were found to have a variety of different effects on the protein structure, with some species showing altered packing of regular secondary structure elements, while other mutants showed no or only strictly localized changes of the structure near the variant amino acid. The fact that some of the disease-related amino acid exchanges cause no measurable change of the PrP(C) structure indicates that their influence on the conformational transition to the scrapie form of PrP may be due to modified intermolecular interactions during the aggregation process.