Flexibility of the murine prion protein and its Asp178Asn mutant investigated by molecular dynamics simulations

TitleFlexibility of the murine prion protein and its Asp178Asn mutant investigated by molecular dynamics simulations
Publication TypeJournal Article
Year of Publication2001
AuthorsGsponer J., Ferrara P., Caflisch A.
JournalJournal of Molecular Graphics and Modelling
Date Published2001
Type of ArticleResearch Article
KeywordsAnimals, Computer Simulation, Hydrogen Bonding, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Point Mutation, Prions, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Thermodynamics

Inherited forms of transmissible spongiform encephalopathy, e.g. familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia, segregate with specific point mutations of the prion protein. It has been proposed that the pathologically relevant Asp178Asn (D178N) mutation might destabilize the structure of the prion protein because of the loss of the Arg164-Asp178 salt bridge. Molecular dynamics simulations of the structured C-terminal domain of the murine prion protein and the D178N mutant were performed to investigate this hypothesis. The D178N mutant did not deviate from the NMR conformation more than the wild type on the nanosecond time scale of the simulations. In agreement with CD spectroscopy experiments, no major structural rearrangement could be observed for the D178N mutant, apart from the N-terminal elongation of helix 2. The region of structure around the disulfide bridge deviated the least from the NMR conformation and showed the smallest fluctuations in all simulations in agreement with hydrogen exchange data of the wild type prion protein. Large deviations and flexibility were observed in the segments which are ill-defined in the NMR conformation. Moreover, helix 1 showed an increased degree of mobility, especially at its N-terminal region. The dynamic behavior of the D178N mutant and its minor deviation from the folded conformation suggest that the salt bridge between Arg164 and Asp178 might not be crucial for the stability of the prion protein.



Alternate JournalJ. Mol. Graph. Model.
PubMed ID11775003
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