capable, however, of binding the entire four-helix bundle of the trans-SNARE complex. One hypothesis suggests that, during SNARE-complex assembly, the Munc18 clasp releases closed syntaxin, remains associated with the N-terminal peptide of syntaxin (allowing association of the syntaxin SNARE domain with other SNARE proteins), and then reattaches to the newly formed four-helix SNARE complex. This possible mechanism of dissociation and subsequent re-association with the SNARE domains could be calcium-dependent. This supports the idea that Munc18 plays a key regulatory role in vesicle fusion; under normal conditions the SNARE complex will be prevented from forming by Munc18, but when triggered the Munc18 will actually assist in SNARE-complex assembly and thereby act as a fusion catalyst. Zippering and fusion pore opening Membrane fusion is an energetically demanding series of events, which requires translocation of proteins in the membrane and disruption of the lipid bilayer, followed by reformation of a highly curved membrane structure. The process of bringing together two membranes requires input energy to overcome the repulsive electrostatic forces between the membranes. The mechanism that regulates the movement of membrane associated proteins away from the membrane contact zone prior to fusion is unknown, but the local increase in membrane curvature is thought to contribute in the process. SNAREs generate energy through protein-lipid and protein-protein interactions which act as a driving force for membrane fusion. One model hypothesizes that the force required to bring two membranes together during fusion comes from the conformational change in trans-SNARE complexes to form cis-SNARE complexes. The current hypothesis that describes this process is referred to as SNARE "zippering." When the trans-SNARE complex is formed, the SNARE proteins are still found on opposing membranes. As the SNARE domains continue coiling in a spontaneous process, they form a much tighter, more stable four-helix bundle. During this "zippering" of the SNARE complex, a fraction of the released energy from binding is thought to be stored as molecular bending stress in the individual SNARE motifs. This mechanical stress is postulated to be stored in the semi-rigid linker regions between the transmembrane domains and the SNARE helical bundle. The energetically unfavorable bending is minimized when the complex moves peripherally to the site of membrane fusion. As a result, relief of the stress overcomes the repulsive forces between the vesicle and the cell membrane and presses the two membranes together. Several models to explain the subsequent step – the formation of stalk and