Abstract
We have performed molecular dynamics simulations on the human prion protein to study the effect of point mutations in relation to the inherited form of Creutzfeldt-Jakob disease. Three model structures of the human prion protein are examined with a focus on their dynamics and conformational changes. Model 1 is an NMR structure of the globular domain (125-228) of a wild-type prion. The model consists of three α-helices and an anti-parallel β-sheet. Models 2 and 3 are mutant structures containing a Glu200→Asp and a Glu200→Lys substitution, respectively. These models are derived from NMR structures. The Glu200→Lys in model 3 is a disease-related amino acid exchange. The results of about 2-million time step calculations have shown that the globular domains of models 1 and 2 are stable, whereas, for model 3, we observe a partial unfolding and reorganization of the protein structure by insertion of the disease-related mutation Glu200→Lys.
