Coupling of Ca2+-triggered unclamping and membrane fusion during neurotransmitter release

Neurotransmitter (NT) release is accomplished by a machinery that unclamps fusion in response to calcium and then fuses the synaptic vesicle and plasma membranes. These are often thought of as distinct tasks assigned to non-overlapping components. Vesicle release rates have a power law dependence on [Ca2+] with an exponent of 3-5, long taken to indicate that 3-5 Ca2+ ions bind the calcium sensor Synaptotagmin to trigger release. However, dependencies at low [Ca2+] are inconsistent with simple sequential binding to a single Ca2+ sensor followed by a final fusion step. Here we developed coarse-grained molecular dynamics simulations of the NT release machinery accounting for Synaptotagmin-mediated unclamping and SNARE-mediated fusion. Calcium-triggered unclamping and SNARE-mediated fusion emerged from simulations as contemporaneous, coupled processes. Increasing cytosolic [Ca2+], the instantaneous fusion rate increased as SNAREpins were progressively and reversibly released by dissociation of Synaptotagmin-SNAREpin complexes. Simulations reproduced the observed dependence of release rates on [Ca2+], but the power law was unrelated to the number of Ca2+ ions required. Action potential-evoked vesicle release probabilities depended on the number of transiently unclamped SNAREpins, explaining experimental dependencies of release probabilities on both unclamping and membrane-fusing machinery components. These results describe a highly cooperative NT release machinery with intrinsically inseparable unclamping and membrane-fusing functionalities.

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SNAREs and Synaptotagmin cooperatively determine the Ca2+ sensitivity of neurotransmitter release in fixed stoichiometry modules

10.1101/2021.06.22.449527 ◽

2021 ◽

Author(s):

Zachary A McDargh ◽

Ben A O'Shaughnessy

Keyword(s):

Molecular Dynamics ◽

Neurotransmitter Release ◽

Release Site ◽

Snare Complex ◽

Snare Proteins ◽

Stoichiometric Ratio ◽

Release Rates ◽

Vesicle Tethering ◽

Fusion Site ◽

Dynamics Simulations

Neurotransmitter release is accomplished by a multi-component machinery including the membrane-fusing SNARE proteins and Ca2+-sensing Synaptotagmin molecules. However, the Ca2+ sensitivity of release was found to increase or decrease with more or fewer SNARE complexes at the release site, respectively, while the cooperativity is unaffected (Acuna et al., 2014; Arancillo et al., 2013), suggesting that there is no simple division of labor between these two components. To examine the mechanisms underlying these findings, we developed molecular dynamics simulations of the neurotransmitter release machinery, with variable numbers of Synaptotagmin molecules and assembled SNARE complexes at the release site. Ca2+ uncaging simulations showed that increasing the number of SNARE complexes at fixed stoichiometric ratio of Synaptotagmin to SNAREs increased the Ca2+ sensitivity without affecting the cooperativity. The physiological cooperativity of ~4-5 was reproduced with 2-3 Synaptotagmin molecules per SNARE complex, suggesting that Synaptotagmin and SNAREs cooperate in fixed stoichiometry modules. In simulations of action potential-evoked release, increased numbers of Synaptotagmin-SNARE modules increased release probability, consistent with experiment. Our simulations suggest that the final membrane fusion step is driven by SNARE complex-mediated entropic forces, and by vesicle-tethering forces mediated by the long Synaptotagmin linker domains. In consequence, release rates are increased when more SNARE complexes and Synaptotagmin monomers are present at the fusion site.

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All-atom molecular dynamics simulations of synaptic vesicle fusion I: a glimpse at the primed state

10.1101/2021.12.29.474428 ◽

2021 ◽

Author(s):

Josep Rizo ◽

Levent Sari ◽

Yife Qi ◽

Wonpil Im ◽

Milo M Lin

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Neurotransmitter Release ◽

Synaptic Vesicles ◽

Plasma Membranes ◽

Synaptotagmin 1 ◽

Primed State ◽

Dynamics Simulations ◽

Synaptic Vesicle Fusion ◽

Shed Light

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 help visualize potential states of the release machinery en route to fusion, and suggest mechanistic features that may control the speed of release. In particular, the simulations suggest that the primed state contains almost fully assembled trans-SNARE complexes bound to the synaptotagmin-1 C2B domain and complexin-1 in a spring-loaded configuration where interactions of the C2B domain with the plasma membrane orient complexin-1 toward the vesicle, avoiding premature membrane merger but keeping the system ready for fast fusion upon Ca2+ influx.

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Parameterization of Divalent Cations for Coarse-Grained Simulations

10.26434/chemrxiv.11881716 ◽

2020 ◽

Author(s):

Florencia Klein ◽

Daniela Cáceres-Rojas ◽

Monica Carrasco ◽

Juan Carlos Tapia ◽

Julio Caballero ◽

...

Keyword(s):

Molecular Dynamics ◽

Metal Ions ◽

Molecular Dynamics Simulations ◽

Divalent Cations ◽

Computational Cost ◽

Data Bank ◽

Coarse Grained ◽

Interaction Parameters ◽

Dynamics Simulations ◽

Dynamical Description

<p>Although molecular dynamics simulations allow for the study of interactions among virtually all biomolecular entities, metal ions still pose significant challenges to achieve an accurate structural and dynamical description of many biological assemblies. This is particularly the case for coarse-grained (CG) models. Although the reduced computational cost of CG methods often makes them the technique of choice for the study of large biomolecular systems, the parameterization of metal ions is still very crude or simply not available for the vast majority of CG- force fields. Here, we show that incorporating statistical data retrieved from the Protein Data Bank (PDB) to set specific Lennard-Jones interactions can produce structurally accurate CG molecular dynamics simulations. Using this simple approach, we provide a set of interaction parameters for Calcium, Magnesium, and Zinc ions, which cover more than 80% of the metal-bound structures reported on the PDB. Simulations performed using the SIRAH force field on several proteins and DNA systems show that using the present approach it is possible to obtain non-bonded interaction parameters that obviate the use of topological constraints. </p>

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Understanding the mechanical and viscoelastic properties of graphene reinforced polycarbonate nanocomposites using coarse-grained molecular dynamics simulations

Computational Materials Science ◽

10.1016/j.commatsci.2021.110339 ◽

2021 ◽

Vol 191 ◽

pp. 110339

Author(s):

Jie Yang ◽

Daniel Custer ◽

Cho Chun Chiang ◽

Zhaoxu Meng ◽

X.H. Yao

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Viscoelastic Properties ◽

Coarse Grained ◽

Dynamics Simulations ◽

Coarse Grained Molecular Dynamics

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Molecular Dynamics Simulations of Ion-Containing Polymers Using Generic Coarse-Grained Models

Macromolecules ◽

10.1021/acs.macromol.0c02557 ◽

2021 ◽

Vol 54 (5) ◽

pp. 2031-2052 ◽

Cited By ~ 1

Author(s):

Kuan-Hsuan Shen ◽

Mengdi Fan ◽

Lisa M. Hall

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Coarse Grained ◽

Dynamics Simulations

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Variation of Interaction Zone Size For The Target Design of 2D Supramolecular Networks

Molecular Systems Design & Engineering ◽

10.1039/d1me00068c ◽

2021 ◽

Author(s):

Łukasz Piotr Baran ◽

Wojciech Rżysko ◽

Dariusz Tarasewicz

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Self Assembly ◽

The Self ◽

Coarse Grained ◽

Zone Size ◽

Interaction Zone ◽

Supramolecular Networks ◽

Dynamics Simulations ◽

Target Design

In this study we have performed extensive coarse-grained molecular dynamics simulations of the self-assembly of tetra-substituted molecules. We have found that such molecules are able to form a variety of...

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