TCB Publications - Abstract

Josh V. Vermaas and Emad Tajkhorshid. Conformational heterogeneity of α-synuclein in membrane. Biochimica et Biophysica Acta - Biomembranes, 1838:3107-3117, 2014. (PMC: PMC4194229)

VERM2014A-ET $\alpha$-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.

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