SNARE-mediated membrane fusion is a two-stage process driven by entropic forces.

SNARE proteins constitute the core of the exocytotic membrane fusion machinery. Fusion occurs when vesicle-associated and target membrane-associated SNAREs zipper into trans-SNARE complexes ('SNAREpins'), but the number required is controversial and the mechanism of cooperative fusion is poorly understood. We developed a highly coarse-grained molecular dynamics simulation to access the long fusion timescales, which revealed a two-stage process. First, zippering energy was dissipated and cooperative entropic forces assembled the SNAREpins into a ring; second, entropic forces expanded the ring, pressing membranes together and catalyzing fusion. We predict that any number of SNAREs fuses membranes, but fusion is faster with more SNAREs.