Vermaas, Josh V.; Tajkhorshid, Emad
Conformational heterogeneity of alpha-synuclein in membrane

alpha-Synuclein (alpha S) is a natively disordered protein in solution, thought to be involved in the fusion of neurotransmitter vesicles to cellular membranes during neurotransmission. Monomeric alpha S 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 alpha S and the conformational dynamics of monomeric alpha S in its membrane-bound form. By repeatedly placing helical alpha S 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 alpha S in its membrane-bound state, suggesting that alpha S has a highly variable membrane insertion depth at equilibrium. Our simulations also capture two distinct states of alpha S, the starting broken-helix conformation seen in the micelle bound NMR structures, and a semi-extended helix. Analysis of lipid distributions near alpha S 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 alpha S may also occur in vivo, and may be important for the physiological function of alpha S. (C) 2014 Elsevier B.V. All rights reserved.


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