All-atom molecular dynamics simulations of synaptic vesicle fusion I: a glimpse at the primed Synaptotagmin-SNARE-complexin complex

<p>Synaptic vesicles are primed into a state that is ready for fast neurotransmitter release upon Ca²⁺-binding to Syt1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to Syt1 and complexins. However, the nature of this state and the steps leading to membrane fusion are unclear, in part because of the difficulty of studying this dynamic process experimentally. To shed light into these questions, we performed all-atom molecular dynamics simulations of systems containing trans-SNARE complexes between two flat bilayers or a vesicle and a flat bilayer with or without fragments of Syt1 and/or complexin-1. Our results need to be interpreted with caution because of the limited simulation times and the absence of key components, but suggest mechanistic features that may control release and help visualize potential states of the primed Syt1-SNARE-complexin-1 complex. In particular, the simulations suggest that SNAREs alone induce formation of extended membrane-membrane contact interfaces that may fuse slowly, and that the primed state contains macromolecular assemblies of trans-SNARE complexes bound to the Syt1 C₂B domain and complexin-1 in a spring-loaded configuration that prevents premature membrane merger and formation of extended interfaces but keeps the system ready for fast fusion upon Ca²⁺ influx.</p>