SNARE proteins are the core of the cell’s fusion machinery and
mediate virtually all known intracellular membrane fusion reactions
on which exocytosis and trafficking depend. Fusion is catalyzed when
vesicle-associated v-SNAREs form trans-SNARE complexes (“SNAREpins”)
with target membrane-associated t-SNAREs, a zippering-like
process releasing ∼65 kT per SNAREpin. Fusion requires several SNAREpins,
but how they cooperate is unknown and reports of the number
required vary widely. To capture the collective behavior on the long
timescales of fusion, we developed a highly coarse-grained model that
retains key biophysical SNARE properties such as the zippering energy
landscape and the surface charge distribution. In simulations the
∼65-kT zippering energy was almost entirely dissipated, with fully
assembled SNARE motifs but uncomplexed linker domains. The
SNAREpins self-organized into a circular cluster at the fusion site,
driven by entropic forces that originate in steric–electrostatic interactions
among SNAREpins and membranes. Cooperative entropic
forces expanded the cluster and pulled the membranes together
at the center point with high force. We find that there is no critical
number of SNAREs required for fusion, but instead the fusion rate
increases rapidly with the number of SNAREpins due to increasing
entropic forces. We hypothesize that this principle finds physiological
use to boost fusion rates to meet the demanding timescales of
neurotransmission, exploiting the large number of v-SNAREs available
in synaptic vesicles. Once in an unfettered cluster, we estimate
≥15 SNAREpins are required for fusion within the ∼1-ms
timescale of neurotransmitter release
