  The relevance of various residue positions for the stability and the folding
characteristics of the prion protein are investigated by using molecular
dynamics simulations of models exploiting the topology of the native state.
Highly significant correlations are found between the most relevant sites in
our analysis and the single point mutations known to be associated with the
arousal of the genetic forms of prion disease (caused by the conformational
change from the cellular to the scrapie isoform). Considerable insight into the
conformational change is provided by comparing the folding process of prion and
doppel (a newly discovered protein) sharing very similar native state topology:
the folding pathways of the former can be grouped in two main classes according
to which tertiary structure contacts are formed first enroute to the native
state. For the latter a single class of pathways leads to the native state. Our
results are consistent and supportive of the recent experimental findings that
doppel lacks the scrapie isoform and that such remarkably different behavior
results from differences in the region containing the two $\beta-$strands and
the intervening helix.
