All-atom molecular dynamics simulations of Synaptotagmin-SNARE-complexin complexes bridging a vesicle and a flat lipid bilayer
Synaptic vesicles are primed into a state that is ready for fast neurotransmitter release upon Ca2+-binding to Synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to Synaptotagmin-1 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 Synaptotagmin-1 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 Synaptotagmin-1-SNARE-complexin-1 complex. 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 Synaptotagmin-1 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.
Most files corresponding to our molecular dynamics simulations are available in the dryad database (doi:10.5061/dryad.ns1rn8pw6). Because of the very large size of trajectory files, it was not practical to deposit them in this database, but these files are available from the corresponding author upon reasonable request.
Data from: All-atom molecular dynamics simulations of Synaptotagmin-SNARE-complexin complexes bridging a vesicle and a flat lipid bilayerDryad Digital Repository, doi:10.5061/dryad.ns1rn8pw6.
Article and author information
National Institute of Neurological Disorders and Stroke (R35 NS097333)
- Josep Rizo
Welch Foundation (I-1304)
- Josep Rizo
National Science Foundation (MCB-2111728)
- Wonpil Im
Natural Science Foundation of Shanghai Grant (19ZR1473600)
- Yife Qi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Frederic Pincet, Ecole Normal Superieure, France
- Received: December 14, 2021
- Preprint posted: December 29, 2021 (view preprint)
- Accepted: June 15, 2022
- Accepted Manuscript published: June 16, 2022 (version 1)
- Version of Record published: June 28, 2022 (version 2)
© 2022, Rizo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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