  SNARE proteins zipper to form SNAREpins that power vesicle fusion with target
membranes in a variety of biological processes. A single SNAREpin takes about 1
second to fuse two bilayers, yet a handful can ensure release of
neurotransmitters from synaptic vesicles much faster, in a 10th of a
millisecond. We propose that, similar to the case of muscle myosins, the
ultrafast fusion results from cooperative action of many SNAREpins. The
coupling originates from mechanical interactions induced by confining
scaffolds. Each SNAREpin is known to have enough energy to overcome the fusion
barrier of 25-35 kB T, however, the fusion barrier only becomes relevant when
the SNAREpins are nearly completely zippered and from this state each SNAREpin
can deliver only a small fraction of this energy as mechanical work. Therefore
they have to act cooperatively and we show that at least 3 of them are needed
to ensure fusion in less than a millisecond. However, to reach the pre-fusion
state collectively, starting from the experimentally observed half-zippered
metastable state, the SNAREpins have to mechanically synchronize which takes
exponentially longer time as the number of SNAREpins increases. Incorporating
this somewhat counter-intuitive idea in a simple coarse grained model results
in the novel prediction that there should be an optimum number of SNAREpins for
sub-ms fusion: 3-6 over a wide range of parameters. Interestingly, in situ
cryo-electron microscope tomography has very recently shown that exactly six
SNAREpins participate in the fusion of each synaptic vesicle. This number is in
the range predicted by our theory.
