Point mutations in the human
prion protein gene, leading to amino acid substitutions in the human
prion protein contribute to conversion of PrPC to PrPSc and
amyloid formation, resulting in
prion diseases such as
familial Creutzfeldt-Jakob disease (CJD),
Gerstmann-Straussler-Scheinker disease (GSS), and
fatal familial insomnia. We have investigated impressions of prevalent mutations including Q217R, D202N, F198S, on the human
prion protein and compared the mutant models with wild types. Structural analyses of models were performed with molecular modeling and molecular dynamics simulation methods. According to our results, frequently occurred mutations are observed in conserved and fully conserved sequences of human
prion protein and the most fluctuation values occur in the Helix 1 around residues 144-152 and C-terminal end of the Helix 2. Our analysis of results obtained from MD simulation clearly shows that this long-range effect plays an important role in the conformational fluctuations in mutant structures of human
prion protein. Results obtained from molecular modeling such as creation or elimination of some hydrogen bonds, increase or decrease of the accessible surface area and molecular surface, loss or accumulation of negative or positive charges on specific positions, and altering the polarity and pKa values, show that
amino acid point mutations, though not urgently change the stability of PrP, might have some local impacts on the
protein interactions which are required for oligomerization into fibrillar species.