Molecular mechanism of fusion pore formation driven by the neuronal SNARE complex

Abstract

Release of neurotransmitters from synaptic vesicles begins with narrow fusion pore, the structure of which remains unresolved. T obtain a structural model of the fusion pore, we performed coarse grained molecular dynamics simulations of fusion between nanodisc and a planar bilayer bridged by four partially unzippe SNARE complexes. The simulations revealed that zipping of SNAR complexes pulls the polar C-terminal residues of the synaptobrevi 2 and syntaxin 1A transmembrane domains to form a hydrophili core between the two distal leaflets, inducing fusion pore forma tion. The estimated conductances of these fusion pores are in goo agreement with experimental values. Two SNARE protein mutant inhibiting fusion experimentally produced no fusion pore forma tion. In simulations in which the nanodisc was replaced by a 40-nm vesicle, an extended hemifusion diaphragm formed but a fusio pore did not, indicating that restricted SNARE mobility is require for rapid fusion pore formation. Accordingly, rapid fusion por formation also occurred in the 40-nm vesicle system when SNAR mobility was restricted by external forces. Removal of the restrictio is required for fusion pore expansion.