Simulations on physiological timescales show SNAREs drive membrane fusion by entropic forces

SNARE proteins are the core of the cellular machinery that fuses membranes for fundamental processes such as neurotransmitter or hormone release. The mechanism of SNARE-mediated fusion is controversial. Fusion is widely thought driven by the ∼60 kT zippering energy of SNARE complexation, and a minimum number of SNAREs is thought required. However, experiment suggests complexation occurs after microseconds (Kubelka et al., 2004; Xi et al., 2012), much faster than the millisecond timescales of fusion, and the reported numerical requirements vary widely.