title: The intrinsic stability of the human prion β-sheet region investigated by molecular dynamics.
abstract: Human prion diseases are neurodegenerative disorders associated to the misfolding of the prion protein (PrP). Common features of prion disorders are the fibrillar amyloid deposits and the formation of prefibrillar oligomeric species also suggested as the origin of cytotoxicity associated with diseases. Although the process of PrP misfolding has been extensively investigated, many crucial aspects of this process remain unclear. We have here carried out a molecular dynamics study to evaluate the intrinsic dynamics of PrP β-sheet, a region that is believed to play a crucial role in prion aggregation. Moreover, as this region mediates protein association in dimeric assemblies frequently observed in prion crystallographic investigations, we also analyzed the dynamics of these intermolecular interactions. The extensive sampling of replica exchange shows that the native antiparallel β-structure of the prion is endowed with a remarkable stability. Therefore, upon unfolding, the persistence of a structured β-region may seed molecular association and influence the subsequent phases of the aggregation process. The analysis of the four-stranded β-sheet detected in the dimeric assemblies of PrP shows a tendency of this region to form dynamical structured states. The impact on the β-sheet structure and dynamics of disease associated point mutations has also been evaluated.
authors.affiliation: Division of Molecular Biosciences, Imperial College South Kensington Campus, London, SW7 2AZ, UK.
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.forename: Francesca
authors.initials: F
authors.lastname: Stanzione
authors.forename: Daniela
authors.initials: D
authors.lastname: Marasco
authors.forename: Luigi
authors.initials: L
authors.lastname: Vitagliano
authors.forename: Luciana
authors.initials: L
authors.lastname: Esposito
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D055550:Protein Stability; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D011328:Prions