title: Massive conformation change in the prion protein: Using dual-basin structure-based models to find misfolding pathways.
abstract: We employ all-atom structure-based models with a force field with multiple energetic basins for the C-terminal (residues 166-226) of the mammalian prion protein. One basin represents the known alpha-helical (αH) structure while the other represents the same residues in a left-handed beta-helical (LHBH) conformation. The LHBH structure has been proposed to help describe one class of in vitro grown fibrils, as well as possibly self-templating the conversion of normal cellular prion protein to the infectious form. Yet, it is unclear how the protein may make this global rearrangement. Our results demonstrate that the conformation changes are not strongly limited by large-scale geometry modification and that there may exist an overall preference for the LHBH conformation. Furthermore, our model presents novel intermediate trapping conformations with twisted LHBH structure.
authors.affiliation: Department of Physics and the Institute for Complex Adaptive Matter, University of California at Davis, Davis, California 95616, USA. jsingh@physics.ucdavis.edu
authors.forename: Jesse P
authors.initials: JP
authors.lastname: Singh
authors.forename: Paul C
authors.initials: PC
authors.lastname: Whitford
authors.forename: N R
authors.initials: NR
authors.lastname: Hayre
authors.forename: José
authors.initials: J
authors.lastname: Onuchic
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cox
mesh_terms: D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability
chemical_list: D004220:Disulfides; D011328:Prions