title: Mechanism of copper(II)-induced misfolding of Parkinson's disease protein.
abstract: α-synuclein (aS) is a natively unfolded pre-synaptic protein found in all Parkinson's disease patients as the major component of fibrillar plaques. Metal ions, and especially Cu(II), have been demonstrated to accelerate aggregation of aS into fibrillar plaques, the precursors to Lewy bodies. In this work, copper binding to aS is investigated by a combination of quantum and molecular mechanics simulations. Starting from the experimentally observed attachment site, several optimized structures of Cu-binding geometries are examined. The most energetically favorable attachment results in significant allosteric changes, making aS more susceptible to misfolding. Indeed, an inverse kinematics investigation of the configuration space uncovers a dynamically stable β-sheet conformation of Cu-aS that serves as a nucleation point for a second β-strand. Based on these findings, we propose an atomistic mechanism of copper-induced misfolding of aS as an initial event in the formation of Lewy bodies and thus in PD pathogenesis.
authors.affiliation: Center for High Performance Simulation and Department of Physics, North Carolina State University, Raleigh, North Carolina 27695-7518, USA.
authors.forename: Frisco
authors.initials: F
authors.lastname: Rose
authors.forename: Miroslav
authors.initials: M
authors.lastname: Hodak
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bernholc
mesh_terms: D001665:Binding Sites; D003300:Copper / Q000737:chemistry*; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D051844:alpha-Synuclein / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D051844:alpha-Synuclein; D003300:Copper