title: Molecular dynamics study of the dominant-negative E219K polymorphism in human prion protein.
abstract: Human prion diseases are associated with misfolding or aggregation of the Human Prion Protein (HuPrP). Missense mutations in the HuPrP gene, contribute to conversion of HuPrP(C) to HuPrP(Sc) and amyloid formation. Based on our previous comprehensive study, three missense mutations, from two different functional groups, i.e. disease-related mutations, and protective mutations, were selected and extensive molecular dynamics simulations were performed on these three mutants to compare their dynamics and conformations with those of the wildtype HuPrP. In addition to simulations of monomeric forms of mutants, in order to study the dominant-negative effect of protective mutation (E219K), 30-ns simulations were performed on E219K-wildtype and wildtype-wildtype dimeric forms. Our results indicate that, although after 30-ns simulations the global three-dimensional structure of models remain fairly intact, the disease-related mutations (V210I and Q212P) introduce local structural changes, i.e. close contact changes and secondary structure changes, in addition to global flexibility changes. Furthermore, our results support the loss of hydrophobic interaction due to the mutations in hydrophobic core that has been reported by previous NMR and computational studies. On the other hand, this protective mutation (E219K) results in helix elongation, and significant increases of overall flexibility of E219K mutant during 30-ns simulation. In conclusion, the simulations of dimeric forms suggest that the dominant-negative effect of this protective mutation (E219K) is due to the incompatible structures and dynamics of allelic variants during conversion process.
authors.affiliation: a Program on Bioinformatics and Systems Biology , Sanford-Burnham Medical Research Institute , La Jolla , CA 92037 , USA.
authors.forename: Samad
authors.initials: S
authors.lastname: Jahandideh
authors.forename: Mostafa
authors.initials: M
authors.lastname: Jamalan
authors.forename: Maryam
authors.initials: M
authors.lastname: Faridounnia
mesh_terms: D000595:Amino Acid Sequence; D003062:Codon; D005799:Genes, Dominant; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D003062:Codon; D011328:Prions
keywords: Creutzfeldt–Jakob Disease (CJD); Gerstmann–Straussler–Scheinker disease (GSS); dominant-negative effect; protective mutation