Conformational heterogeneity of α-synuclein in membrane

Josh V. Vermaas, Emad Tajkhorshid

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)3107-3117
Number of pages11
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number12
StatePublished - Dec 2014


  • HMMM
  • Membrane binding
  • Molecular dynamics
  • Peripheral membrane protein
  • α-Synuclein

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology


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