title: α-Synuclein dimer structures found from computational simulations.
abstract: Dimer formation is likely the first step in the oligomerization of α-synuclein in Lewy bodies. In order to prevent α-synuclein aggregation, knowledge of the atomistic structures of possible α-synuclein dimers and the interaction affinity between the dimer domains is a necessary prerequisite in the process of rational design of dimerization inhibitors. Using computational methodology, we have investigated several possible α-synuclein dimer structures, focusing on dimers formed from α-helical forms of the protein found when it is membrane-bound, and dimers formed from β-sheet conformations predicted by simulations. Structures and corresponding binding affinities for the interacting monomers in possible α-synuclein dimers, along with properties including the contributions from different interaction energies and the radii of gyration, were found through molecular docking followed by MD simulations and binding-energy calculations. We found that even though α-synuclein is highly charged, hydrophobic contributions play a significant role in stabilizing dimers.
authors.affiliation: Department of Physics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Kamlesh Kumar
authors.initials: KK
authors.lastname: Sahu
authors.affiliation: Department of Physics, University of Alberta, Edmonton, AB, Canada; National Institute for Nanotechnology, National Research Council, Edmonton, AB, Canada.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Woodside
authors.affiliation: Department of Physics, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada. Electronic address: jackt@ualberta.ca.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
mesh_terms: D019281:Dimerization; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein
keywords: Alpha-synuclein; Alzheimers; Docking; MMGBSA; Molecular dynamics; Neurodegenerative disease