Fig. 1: Computational implementation of the release of inhibition model.

a At rest, the full zippering of SNAREs on RRP vesicles is inhibited (‘clamped’) by the binding of synaptotagmin and complexin molecules. Based on structural data, three synaptotagmin/SNARE clamp architectures were considered in the model (right). In all cases, Syt1 occupies the primary interface. The tripartite interface is either unoccupied (single clamp, Syt1^P) or occupied (dual clamp) by Syt1 (Syt1^P/Syt1^T) or Syt7 (Syt1^P/Syt7^T). Crystal structure (PDB ID: 5W5C)²¹. b The binding of two Ca²⁺ ions to a synaptotagmin C2 domain leads to its subsequent membrane insertion, described by the Markov kinetic scheme on the right, and release of its SNARE fusion clamp, allowing full zippering of SNAREs which provides energy for membrane fusion. c The rate of SV fusion is determined by the number of free SNARE complexes. These reduce the effective membrane fusion energy barrier, illustrated here as a Gaussian landscape (right). Each SNAREpin was assumed to independently contribute to the lowering of the membrane fusion barrier, which is spontaneously overcome at a rate given by the Arrhenius equation (see “Methods”). Note that only two out of six SNARE complexes are shown in the cartoons on the left that represent a vertical cross-section of the SV.