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

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.