title: Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates.
abstract: The Josephin Domain (JD), i.e. the N-terminal domain of Ataxin 3 (At3) protein, is an interesting example of competition between physiological function and aggregation risk. In fact, the fibrillogenesis of Ataxin 3, responsible for the spinocerebbellar ataxia 3, is strictly related to the JD thermodynamic stability. Whereas recent NMR studies have demonstrated that different JD conformations exist, the likelihood of JD achievable conformational states in solution is still an open issue. Marked differences in the available NMR models are located in the hairpin region, supporting the idea that JD has a flexible hairpin in dynamic equilibrium between open and closed states. In this work we have carried out an investigation on the JD conformational arrangement by means of both classical molecular dynamics (MD) and Metadynamics employing essential coordinates as collective variables. We provide a representation of the free energy landscape characterizing the transition pathway from a JD open-like structure to a closed-like conformation. Findings of our in silico study strongly point to the closed-like conformation as the most likely for a Josephin Domain in water.
authors.affiliation: Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Manno, Switzerland.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Deriu
authors.affiliation: Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Manno, Switzerland.
authors.forename: Gianvito
authors.initials: G
authors.lastname: Grasso
authors.affiliation: Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
authors.affiliation: Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Torino, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Gallo
authors.affiliation: Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Torino, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Morbiducci
authors.affiliation: Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Manno, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Danani
mesh_terms: D000067699:Ataxin-3 / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D000067699:Ataxin-3