title: A highly tilted membrane configuration for the prefusion state of synaptobrevin.
abstract: The SNARE complex plays a vital role in vesicle fusion arising during neuronal exocytosis. Key components in the regulation of SNARE complex formation, and ultimately fusion, are the transmembrane and linker regions of the vesicle-associated protein, synaptobrevin. However, the membrane-embedded structure of synaptobrevin in its prefusion state, which determines its interaction with other SNARE proteins during fusion, is largely unknown. This study reports all-atom molecular-dynamics simulations of the prefusion configuration of synaptobrevin in a lipid bilayer, aimed at characterizing the insertion depth and the orientation of the protein in the membrane, as well as the nature of the amino acids involved in determining these properties. By characterizing the structural properties of both wild-type and mutant synaptobrevin, the effects of C-terminal additions on tilt and insertion depth of membrane-embedded synaptobrevin are determined. The simulations suggest a robust, highly tilted state for membrane-embedded synaptobrevin with a helical connection between the transmembrane and linker regions, leading to an apparently new characterization of structural elements in prefusion synaptobrevin and providing a framework for interpreting past mutation experiments.
authors.affiliation: Center for Biophysics and Computational Biology, Department of Physics, Department of Biochemistry, College of Medicine and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Blanchard
authors.affiliation: Center for Biophysics and Computational Biology, Department of Physics, Department of Biochemistry, College of Medicine and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arcario
authors.affiliation: Center for Biophysics and Computational Biology, Department of Physics, Department of Biochemistry, College of Medicine and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.affiliation: Center for Biophysics and Computational Biology, Department of Physics, Department of Biochemistry, College of Medicine and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois. Electronic address: emad@life.illinois.edu.
authors.forename: Emad
authors.initials: E
authors.lastname: Tajkhorshid
mesh_terms: D000595:Amino Acid Sequence; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010713:Phosphatidylcholines / Q000737:chemistry; D050683:R-SNARE Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D050683:R-SNARE Proteins; C028694:1-palmitoyl-2-oleoylphosphatidylcholine