Directional Bias in Membrane Fusion: The Role of Tension and Asymmetry

Membrane fusion and fission are topological transitions necessary for various biological processes. The energy barriers to these reactions, usually associated with highly curved membrane necks and in-plane shearing of the lipids’ tails, determine their kinetics. In the context of viral infection, fusion is an essential step for enveloped viruses, which must merge their membrane with the host cell to deliver their genome. Evolution has optimized the viral fusion machinery, matrix layer disassembly, and viral shape to minimize energy barriers and enhance entry efficiency. Host cells counteract viral invasion by regulating membrane properties to increase these barriers, a form of mechanical immunity.

A key challenge in cellular defense is that fusion and fission are also essential for intracellular processes such as vesicle trafficking and organelle maturation. Therefore, cells must have evolved a mechanism for fusion bias—on the one hand, inhibiting viral entry from the extracellular side, while on the other, promoting necessary fusion processes from the intracellular side. Here, using a combination of continuum modeling and simulations, we show that manipulating membrane tension and inducing conical lipid composition asymmetry can provide such a mechanism. Our numerical results predict that the observed asymmetry and tension in red blood cells’ external membranes result in a 20 kBT difference in the energy barrier for fusion from the two sides of the membrane, favoring fusion from the intracellular side. We further provide experimental support for these predictions by manipulating tension, lipid composition, and composition asymmetry in synthetic giant unilamellar vesicles (GUVs) and measuring their hemifusion time with membrane-coated beads, which agrees well with the theoretical predictions.