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Prevalent mutations of human prion protein: a molecular modeling and molecular dynamics study.

Abstract
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.
AuthorsEsmaeil Behmard, Parviz Abdolmaleki, Ebrahim Barzegari Asadabadi, Samad Jahandideh
JournalJournal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 29 Issue 2 Pg. 379-89 (Oct 2011) ISSN: 1538-0254 [Electronic] England
PMID21875156 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Prions
Topics
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Humans
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutation Rate
  • Prions (chemistry, genetics)
  • Protein Structure, Secondary
  • Sequence Alignment

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