Theoretical and Computational Chemistry

Enhanced Expansion and Reduced Kiss-and-Run in Fusion Pores Steered by Synaptotagmin-1 C2B Domains



The fusion pore controls the release of exocytotic vesicles contents through a precise orchestration of lipids from the fusing membranes and proteins. There is a major lipid reorganization during the different stages in life of the fusion pore: membrane fusion, nucleation and expansion, that can be scrutinized thermodynamically. In this work, using restrained molecular dynamics simulations we describe the expansion of the fusion pore. We have calculated free energy profiles to drive a nascent, just nucleated, fusion pore to its expanded configuration. We have quantified the effects on the free energy of one and two Synaptotagmin-1 C2B domains in the cytosolic space. We show that C2B domains cumulatively reduce the cost for expansion, favoring the system to evolve towards full fusion. Finally, by conducting thousands of unbiased molecular dynamics simulations, we show that C2B domains significantly decrease the probability of kiss-and-run events.


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Supplementary material

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Supporting Information
Supporting information includes: umbrella sampling technical details and convergence analyses; mathematical details for the calculation of the volume in the toroid-shaped fusion pore; input files for PLUMED to conduct restrained molecular dynamics using the collective variable.
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Water molecules showing fusion pore nucleation + expansion
Video shows intra-organelle water beads in blue and cytosolic water beads in gray. Under the action of the collective variable, the fusion pore continuously nucleates and expands.