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

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