Molecular mechanism underlying SNARE-mediated membrane fusion enlightened by all-atom molecular dynamics simulations

The SNARE proteins syntaxin-1, SNAP-25 and synaptobrevin mediate neurotransmitter release by forming tight SNARE complexes that fuse synaptic vesicles with the plasma membranes in microseconds. Membrane fusion is generally explained by the action of proteins on macroscopic membrane properties such as curvature, elastic modulus and tension, and a widespread model envisions that the SNARE motifs, juxtamembrane linkers and C-terminal transmembrane regions of synaptobrevin and syntaxin-1 form continuous helices that act mechanically as semi-rigid rods, squeezing the membranes together as they assemble (‘zipper’) from the N- to the C-termini. However, the mechanism underlying fast SNARE-induced membrane fusion remains unknown. We have used all-atom molecular dynamics simulations to investigate this mechanism. Our results need to be interpreted with caution because of the limited number and length of the simulations, but they suggest a model of membrane fusion that has a natural physicochemic..., The methodology used in system setups, equilibration and production MD simulations was analogous to that described previously (1). The vesicle generated previously (1) was adapted for each system by moving lipids manually to accommodate different positions of the SNARE TM regions or their absence. A flat square bilayer of 30.5 nm x 30.5 nm was built at the CHARMM-GUI website (2) (https://charmm-gui.org/) for the fusion2g system and was adapted for all other systems (also moving lipids manually to accommodate SNARE TM regions) except for the snfreet350 system, which used a smaller bilayer adapted from the qscv simulation of ref. (1). The lipid compositions of the original vesicle and flat bilayers are described in Table 1 of the manuscript, and those of each system were only slightly altered by adding or removing a few lipids as needed. The number of atoms, box dimensions and simulation temperatures of each system are also listed in Table 1 of the manuscript. All systems were solvated wi..., , These data sets contain files associated with all-atom molecular dynamics simulations of the neurotransmitter release machinery between a flat bilayer and a vesicle. The simulations were performed with gromacs. Each directory corresponds to one simulation as described briefly below and with more detail in the reference associated with this deposition (see the results part, figure legends and Table 1 of the reference).

fusion2g: simulation of four almost completely helical trans-SNARE complexes bridging a vesicle and a flat bilayer and close to the center of the interface at 310 K.

t350f2: continuation of the fusion2g simulation but at 350 K.

t350f2e: continuation of the fusion2g simulation but at 350 K after re-centering the system and increasing the box size.

t350f4link: simulation of four trans-SNARE complexes bridging a vesicle and a flat bilayer, with the linkers zippered but no pulling force to keep them zippered at 350 K.

pull4link: simulation of four trans-SNARE complexes br...