title: Conformational fluctuations of the AXH monomer of Ataxin-1.
abstract: In this paper, we report the results of molecular dynamics simulations of AXH monomer of Ataxin-1. The AXH domain plays a crucial role in Ataxin-1 aggregation, which accompanies the initiation and progression of Spinocerebellar ataxia type 1. Our simulations involving both classical and replica exchange molecular dynamics, followed by principal component analysis of the trajectories obtained, reveal substantial conformational fluctuations of the protein structure, especially in the N-terminal region. We show that these fluctuations can be generated by thermal noise since the free energy barriers between conformations are small enough for thermally stimulated transitions. In agreement with the previous experimental findings, our results can be considered as a basis for a future design of ataxin aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding.
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, 6928, Switzerland.
authors.forename: Gianvito
authors.initials: G
authors.lastname: Grasso
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, 6928, Switzerland.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Deriu
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, 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, 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, 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; D066329:Protein Aggregates; D017434:Protein Structure, Tertiary; D020754:Spinocerebellar Ataxias / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000067696:Ataxin-1; D066329:Protein Aggregates
keywords: Ataxin; clustering; free energy; molecular dynamics; molecular modeling; neurodegenerative; principal component analysis; replica exchange