1. Structural Biology and Molecular Biophysics

All-atom molecular dynamics simulations of Synaptotagmin-SNARE-complexin complexes bridging a vesicle and a flat lipid bilayer

  1. Josep Rizo  Is a corresponding author
  2. Levent Sari
  3. Yife Qi
  4. Wonpil Im
  5. Milo M Lin
  1. The University of Texas Southwestern Medical Center, United States
  2. Fudan University, China
  3. Lehigh University, United States
https://doi.org/10.7554/eLife.76356
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  1. Josep Rizo
  2. Levent Sari
  3. Yife Qi
  4. Wonpil Im
  5. Milo M Lin
(2022)
All-atom molecular dynamics simulations of Synaptotagmin-SNARE-complexin complexes bridging a vesicle and a flat lipid bilayer
eLife 11:e76356.
https://doi.org/10.7554/eLife.76356
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Abstract

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.

Data availability

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.

The following data sets were generated

Article and author information

Author details

  1. Josep Rizo

    Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Jose.Rizo-Rey@UTSouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1773-8311

  2. Levent Sari

    Green Center for Systems Biology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Yife Qi

    Department of Medicinal Chemistry, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Wonpil Im

    Department of Biological Sciences, Lehigh University, Bethlehem, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5642-6041

  5. Milo M Lin

    Green Center for Systems Biology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8680-2685

Funding

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.

Copyright

© 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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  1. Josep Rizo
  2. Levent Sari
  3. Yife Qi
  4. Wonpil Im
  5. Milo M Lin
(2022)
All-atom molecular dynamics simulations of Synaptotagmin-SNARE-complexin complexes bridging a vesicle and a flat lipid bilayer
eLife 11:e76356.
https://doi.org/10.7554/eLife.76356

Share this article

https://doi.org/10.7554/eLife.76356

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