title: Mechanical coupling via the membrane fusion SNARE protein syntaxin 1A: a molecular dynamics study.
abstract: SNARE trans complexes between membranes likely promote membrane fusion. For the t-SNARE syntaxin 1A involved in synaptic transmission, the secondary structure and bending stiffness of the five-residue juxtamembrane linker is assumed to determine the required mechanical energy transfer from the cytosolic core complex to the membrane. These properties have here been studied by molecular dynamics and annealing simulations for the wild-type and a C-terminal-prolongated mutant within a neutral and an acidic bilayer, suggesting linker stiffnesses above 1.7 but below 50 x 10(-3) kcal mol(-1) deg(-2). The transmembrane helix was found to be tilted by 15 degrees and tightly anchored within the membrane with a stiffness of 4-5 kcal mol(-1) A(-2). The linker turned out to be marginally helical and strongly influenced by its lipid environment. Charged lipids increased the helicity and H3 helix tilt stiffness. For the wild type, the linker was seen embedded deeply within the polar region of the bilayer, whereas the prolongation shifted the linker outward. This reduced its helicity and increased its average tilt, thereby presumably reducing fusion efficiency. Our results suggest that partially unstructured linkers provide considerable mechanical coupling; the energy transduced cooperatively by the linkers in a native fusion event is thus estimated to be 3-8 kcal/mol, implying a two-to-five orders of magnitude fusion rate increase.
authors.affiliation: Theoretical Molecular Biophysics Group, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Knecht
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
mesh_terms: D000954:Antigens, Surface / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D004548:Elasticity; D004735:Energy Transfer; D006358:Hot Temperature; D008051:Lipid Bilayers / Q000737:chemistry*; D046911:Macromolecular Substances; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D009038:Motion; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010865:Pilot Projects; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D021122:Protein Subunits; D050600:SNARE Proteins; D013314:Stress, Mechanical; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; D014867:Water / Q000737:chemistry
chemical_list: D000954:Antigens, Surface; D008051:Lipid Bilayers; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D050600:SNARE Proteins; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; D014867:Water