title: Enhanced sampling molecular dynamics identifies PrP(Sc) structures harboring a C-terminal β-core.
abstract: We perform a replica exchange molecular dynamics simulation corresponding to a 2.8 μs total time for the extensive enhanced sampling of the conformational space of the C-terminal part (residues 124-226) of the mouse prion protein (PrP); 1.3% of the conformations sampled display a high level of β-structure (≥19 residues), allowing the assessment of β-propensities along the sequence and highlighting the most structurally labile hot spots. A clustering algorithm is applied to sort the structures of this pool according to their fold. Ten β-rich folds are thus defined and analyzed with regard to their topology, accumulation temperatures, and structural characteristics. In contrast to the so-called spiral and β-helix models suggesting that the β-rich core of the scrapie isoform (PrP(Sc)) comprises the N-terminal tail and part of the C-terminal domain up to helix 1 (H1), we present putative structural models for monomeric precursors of PrP(Sc) and PrP β-oligomers that are characterized by a C-terminal β-rich core, in agreement with the suggestions of a series of recent experiments.
authors.affiliation: Laboratory of Computational Chemistry and Biochemistry, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Baillod
authors.forename: Julian
authors.initials: J
authors.lastname: Garrec
authors.forename: Maria-Carola
authors.initials: MC
authors.lastname: Colombo
authors.forename: Ivano
authors.initials: I
authors.lastname: Tavernelli
authors.forename: Ursula
authors.initials: U
authors.lastname: Rothlisberger
mesh_terms: D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D018620:PrPSc Proteins / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D018620:PrPSc Proteins