title: Characterization of the AXH domain of Ataxin-1 using enhanced sampling and functional mode analysis.
abstract: Ataxin-1 is the protein responsible for the Spinocerebellar ataxia type 1, an incurable neurodegenerative disease caused by polyglutamine expansion. The AXH domain plays a pivotal role in physiological functions of Ataxin-1. In Spinocerebellar ataxia 1, the AXH domain is involved in the misfolding and aggregation pathway. Here molecular modeling is applied to investigate the protein-protein interactions contributing to the AXH dimer stability. Particular attention is focused on: (i) the characterization of AXH monomer-monomer interface; (ii) the molecular description of the AXH monomer-monomer interaction dynamics. Technically, an approach based on functional mode analysis, here applied to replica exchange molecular dynamics trajectories, was employed. The findings of this study are consistent with previous experimental results and elucidate the pivotal role of the I580 residue in mediating the AXH monomer-monomer interaction dynamics.
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: 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), Centro Galleria 2, Manno, CH-6928, 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, Corso Duca Degli Abruzzi 24, Torino, IT-10128, Italy.|Department of Cardiothoracic, Transplantation, and Vascular Surgery (HTTG), Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Strabe 1, Hannover, 30625, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Massai
authors.affiliation: Department of Mechanical and Aerospace Engineering, Politecnico Di Torino, Corso Duca Degli Abruzzi 24, Torino, IT-10128, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Gallo
authors.affiliation: Department of Mechanical and Aerospace Engineering, Politecnico Di Torino, Corso Duca Degli Abruzzi 24, Torino, IT-10128, 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), Centro Galleria 2, Manno, CH-6928, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Danani
mesh_terms: D000067696:Ataxin-1 / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072417:Protein Domains; D055550:Protein Stability; D013816:Thermodynamics
chemical_list: D000067696:Ataxin-1
keywords: AXH; Ataxin; conformational stability; dimer; functional mode analysis; neurodegenerative; protein−protein interactions; replica exchange molecular dynamics