Life requires distinct compartments where specialized conditions, biomolecules and processes are maintained. Compartments are typically enclosed by membranes, phospholipid bilayers that are flexible yet impermeable to their aqueous interiors. Since compartmentalization is fundamental to life, so is membrane fusion, which merges compartments. Secretion of neurotransmitters by neurons or insulin by pancreatic beta cells, union of egg and sperm in fertilization and trafficking of lipids and proteins in vesicles to the ingression furrow during cell division are examples of compartment merging by membrane fusion.
A common feature of all intracellular fusion processes is a fusion machinery whose core consists of the SNARE proteins. SNARE-mediated membrane fusion is also measured in model reconstituted experimental systems, and is the basis for attempted drug delivery schemes. Our mathematical models of the fusion machinery, beginning with the SNARE-based core and its interactions with membranes, suggest that entropic forces among SNARE complexes drive their self-organization and generate force that fuses membranes. Thus, more SNAREs cooperatively catalyze fusion faster. Similar entropic forces regulate release rates through the fusion pore once formed, explaining experiments showing that pores are larger when more SNAREs are present.
Understanding membrane fusion is a multiscale and multidisciplinary undertaking. As important as the molecular fusion machinery are the biophysical properties of the membranes which the machinery must steer to fusion. Using analytical and numerical methods we analyze the statistical mechanics of fluctuating membrane surfaces and identify the low energy stable or metastable structures on the pathway to fusion. We established equilibrium laws governing intermediate hemifused structures, and we modeled hemifusion-to-fusion kinetics in calcium driven systems, experimentally studied for decades as model systems for biological fusion.
© O'Shaughnessy Group 2018