title: β-sheet-like formation during the mechanical unfolding of prion protein.
abstract: Single molecule experiments and simulations have been widely used to characterize the unfolding and folding pathways of different proteins. However, with few exceptions, these tools have not been applied to study prion protein, PrP(C), whose misfolded form PrP(Sc) can induce a group of fatal neurodegenerative diseases. Here, we apply novel atomistic modeling based on potential energy surface exploration to study the constant force unfolding of human PrP at time scales inaccessible with standard molecular dynamics. We demonstrate for forces around 100 pN, prion forms a stable, three-stranded β-sheet-like intermediate configuration containing residues 155-214 with a lifetime exceeding hundreds of nanoseconds. A mutant without the disulfide bridge shows lower stability during the unfolding process but still forms the three-stranded structure. The simulations thus not only show the atomistic details of the mechanically induced structural conversion from the native α-helical structure to the β-rich-like form but also lend support to the structural theory that there is a core of the recombinant PrP amyloid, a misfolded form reported to induce transmissible disease, mapping to C-terminal residues ≈160-220.
authors.affiliation: Department of Mechanical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tao
authors.affiliation: Department of Mechanical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Gwonchan
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Department of Mechanical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Penghui
authors.initials: P
authors.lastname: Cao
authors.affiliation: Biomechanics Laboratory, College of Sport Science, Sungkyunkwan University, Suwon 16419, South Korea.
authors.forename: Kilho
authors.initials: K
authors.lastname: Eom
authors.affiliation: Department of Mechanical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Harold S
authors.initials: HS
authors.lastname: Park
mesh_terms: D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D055550:Protein Stability; D017433:Protein Structure, Secondary; D058767:Protein Unfolding
chemical_list: D011328:Prions