Membrane fusion is essential for cell survival and has attracted a great deal of both theoretical and experimental interest. The multiplication of even the simplest, primordial cells relies on the fusion of cellular envelopes. In drug delivery, fusion between a cellular membrane and a lipid-based drug delivery vehicle is critical in order to deliver therapeutic agents directly into the cytosol.

Phospholipid membranes composed of lipid pairs with phosphatidylcholine (PC) and phosphatidic acid (PA) headgroups are known to form phase separated domains at decreasing pH . Phospholipid membranes with non-matching chain lengths were shown by our group to form heterogeneous lipid domains at decreasing pH with leaky interfacial boundaries.In this work, we study the effect of pH-triggered lipid heterogeneities and of cholesterol on the extent of fusion of lipid vesicles. We demonstrate that decrease of pH increases vesicle fusion.

We hypothesize that in these systems intervesicular fusion is driven by the tendency of the system to minimize the total perimeter of the domain/non-domain discontinuous interface. The hydrocarbon chains within the domain/nondomain interface encounter water, since water molecules, being small in size, enter into these discontinuities. This interaction should be entropically unfavorable for the water molecules. Therefore, lipid domains would form larger aggregates in order to minimize the total length of the domain/nondomain interface. We speculate that this effect drives vesicle fusion upon vesicle-vesicle contact. We also demonstrate that the presence of cholesterol decreases the extent of fusion suggesting a potential preference of cholesterol to partition within the interfacial boundaries of lipid heterogeneities or the ability of cholesterol to change the lateral organization of lipids, and, therefore, altering the collective behavior of the separated lipid domains.