title: Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics.
abstract: Molecular phenomena driving pathological aggregation in neurodegenerative diseases are not completely understood yet. Peculiar is the case of Spinocerebellar Ataxia 3 (SCA3) where the conformational properties of the AT-3 N-terminal region, also called Josephin Domain (JD), play a key role in the first step of aggregation, having the JD an amyloidogenic propensity itself. For this reason, unraveling the intimate relationship between JD structural features and aggregation tendency may lead to a step forward in understanding the pathology and rationally design a cure. In this connection, computational modeling has demonstrated to be helpful in exploring the protein molecular dynamics and mechanism of action.
  
  
  
  Conformational dynamics of the JD is here finely investigated by replica exchange molecular dynamics simulations able to sample the microsecond time scale and to provide both a thermodynamic and kinetic description of the protein conformational changes. Accessible structural conformations of the JD have been identified in: open, intermediate and closed like arrangement. Data indicated the closed JD arrangement as the most likely protein arrangement. The protein transition from closed toward intermediate/open states was characterized by a rate constant higher than 700 ns. This result also explains the inability of classical molecular dynamics to explore transitions from closed to open JD configuration on a time scale of hundreds of nanoseconds.
  
  
  
  This work provides the first kinetic estimation of the JD transition pathway from open-like to closed-like arrangement and vice-versa, indicating the closed-like arrangement as the most likely configuration for a JD in water environment. More widely, the importance of our results is also underscored considering that the ability to provide a kinetic description of the protein conformational changes is a scientific challenge for both experimental and theoretical approaches to date.
  
  
  
  This article was reviewed by Oliviero Carugo, Bojan Zagrovic.
authors.affiliation: Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Centro Galleria 2, Manno, CH-6928, Switzerland.
authors.forename: Gianvito
authors.initials: G
authors.lastname: Grasso
authors.affiliation: Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Corso Duca degli Abruzzi 24, IT-10128, Torino, Italy.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
authors.affiliation: Department of Physics, University of Alberta, Edmonton, AB, Canada.
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), Centro Galleria 2, Manno, CH-6928, Switzerland.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Licandro
authors.affiliation: Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Centro Galleria 2, Manno, CH-6928, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Danani
authors.affiliation: Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Centro Galleria 2, Manno, CH-6928, Switzerland. marco.deriu@idsia.ch.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Deriu
mesh_terms: D000067699:Ataxin-3 / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D000067699:Ataxin-3
keywords: Ataxin; Josephin Domain; Kinetics; Neurodegenerative; Protein plasticity; Replica exchange molecular dynamics; Thermodynamics