title: Conformational heterogeneity of α-synuclein in membrane.
abstract: α-Synuclein (αS) is a natively disordered protein in solution, thought to be involved in the fusion of neurotransmitter vesicles to cellular membranes during neurotransmission. Monomeric αS has been previously characterized in two distinct membrane-associated conformations: a broken-helix structure, and an extended helix. By employing atomistic molecular dynamics and a novel membrane representation with significantly enhanced lipid mobility (HMMM), we investigate the process of spontaneous membrane binding of αS and the conformational dynamics of monomeric αS in its membrane-bound form. By repeatedly placing helical αS monomers in solution above a planar lipid bilayer and observing their spontaneous association and its spontaneous insertion into the membrane during twenty independent unbiased simulations, we are able to characterize αS in its membrane-bound state, suggesting that αS has a highly variable membrane insertion depth at equilibrium. Our simulations also capture two distinct states of αS, the starting broken-helix conformation seen in the micelle bound NMR structures, and a semi-extended helix. Analysis of lipid distributions near αS monomers indicates that the transition to a semi-extended helix is facilitated by concentration of phosphatidyl-serine headgroups along the inner edge of the protein. Such a lipid-mediated transition between helix-turn-helix and extended conformations of αS may also occur in vivo, and may be important for the physiological function of αS.
authors.affiliation: Beckman Institute for Advanced Science and Technology, Department of Biochemistry, College of Medicine, and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Josh V
authors.initials: JV
authors.lastname: Vermaas
authors.affiliation: Beckman Institute for Advanced Science and Technology, Department of Biochemistry, College of Medicine, and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: emad@life.illinois.edu.
authors.forename: Emad
authors.initials: E
authors.lastname: Tajkhorshid
keywords: HMMM; Membrane binding; Molecular dynamics; Peripheral membrane protein; α-Synuclein