How SNARE molecules mediate membrane fusion: Recent insights from molecular simulations

► Molecular simulations have revisited the original stalk-pore hypothesis. ► Initial membrane merger is determined by the free energy of leaflet approach. ► SNARE complexes reduce the free energy of leaflet approach and are actively involved in the lipidic transition states. ► SNARE complexes release mechanical stress to actively overcome the barrier against stalk expansion and enforce opening of the fusion pore. ► SNARE complexes can prevent the formation/expansion of a metastable hemifusion diaphragm. SNARE molecules are the core constituents of the protein machinery that facilitate fusion of synaptic vesicles with the presynaptic plasma membrane, resulting in the release of neurotransmitter. On a molecular level, SNARE complexes seem to play a quite versatile and involved role during all stages of fusion. In addition to merely triggering fusion by forcing the opposing membranes into close proximity, SNARE complexes are now seen to also overcome subsequent fusion barriers and to actively guide the fusion reaction up to the expansion of the fusion pore. Here, we review recent advances in the understanding of SNARE-mediated membrane fusion by molecular simulations.