The relevance of various residue positions for the stability and the
folding characteristics of the prion protein in its normal cellular form
are investigated by using molecular dynamics simulations of models
exploiting the topology of the native state. These models allow for
reproducing the experimentally validated two-state behavior of the
normal prion isoform. Highly significant correlations are found between
the most topologically relevant sites in our analysis and the single
point mutations known to be associated with the arousal of the genetic
forms of prion disease. Insight into the conformational change is
provided by comparing the folding process of cellular prion and doppel
that share a 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 again
through a two-state process. Our results are consistent and supportive
of the recent experimental findings that doppel lacks the scrapie
isoform and that such remarkably different behavior involves residues in
the region containing the two beta-strands and the intervening helix.
