Biophysical Society Thematic Meeting| Padova 2019

Quantitative Aspects of Membrane Fusion and Fission

Tuesday Speaker Abstracts

COARSE-GRAINED MATHEMATICAL MODELING OF NEUROTRANSMITTER RELEASE Ben O'Shaughnessy 1 ; 1 Columbia University, Chemical Engineering, New York, New York, USA Tightly synchronized release of neurotransmitters (NTs) from synaptic vesicles at neuronal synapses is accomplished by a machinery that senses Ca when an action potential arrives, fuses the vesicular and plasma membranes, and releases NTs through a fusion pore. Many components of the machinery are now identified, and structural information is emerging. However, it remains a major challenge to understand how the components cooperate as a machine that accomplishes membrane fusion on sub millisecond timescales. Mathematical modeling is needed to help this quest, but describing a machinery comprising tens of proteins on millisecond timescales is currently beyond all-atom or moderately coarse-grained computational approaches. Radical coarse-graining is required. Our approach is molecularly explicit representation based on systematic coarse-graining procedures, sufficiently coarse-grained to access collective behavior on the long timescales of physiological fusion. The framework allows different hypothesized mechanisms to be tested quantitatively. I will describe results that incorporate the calcium sensor Synaptotagmin (Syt) and the SNARE proteins which constitute the core of the fusion machinery. We are testing the hypothesis that ring-like oligomers of Syt clamp fusion by spacing the membranes, until fusion is triggered by calcium-mediated dissociation of the Syt rings (Wang et al., 2014). Simulations describe a 3-stage process: first, calcium-triggered unclamping of the SNAREs as the Syt ring disassembles; second, self-assembly of SNARE complexes into a ring at the fusion site; third, SNARE-mediated membrane fusion. Stages 2 and 3 are driven by entropic forces among the SNAREs and membranes (Mostafavi et al,. 2017; McDargh et al., 2018). Computed release rates versus calcium concentration are compared with experimental electrophysiological measurements.

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