![]() ![]() Fusion is critical for many processes that involve the transport of cargos across membranes such as exocytosis, neurotransmission, infection of cells by enveloped viruses, fertilization, and intracellular transport 5, 6. How complex lipid compositions control the early stages of membrane fusion has not been systematically addressed. Understanding why biological cells synthesize and maintain this complex lipid repertoire, that is, defining the biological function and advantage of specific lipid compositions, remains a central goal of membrane biophysics. Recent lipidomics studies showed that the degree of polyunsaturation in the inner leaflet is approximately twice that of the outer leaflet 4. Apart from different head groups, lipid species differ by the length and unsaturation of the fatty acid tails. In the plasma membrane of mammals, sphingolipids are typically enriched in the outer leaflet of the plasma membrane, whereas phosphatidylethanolamine (PE) and phosphatidylserine (PS) are enriched in the inner leaflet 3. The complexity of membranes is further increased by the membrane asymmetry, that is, by distinct lipid compositions in the two leaflets. In summary, the simulations reveal a drastic influence of the lipid composition on stalk formation and a comprehensive fusogenicity map of many biologically relevant lipid classes.Įukaryotic cellular membranes contain more than ten lipid classes, while each class comprises hundreds of different chemical species 1, 2. ![]() To rationalize these findings by the distinct lipid compositions, we computed ~200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. The method reveals that the inner leaflet of a typical plasma membrane is far more fusogenic than the outer leaflet, which is likely an adaptation to evolutionary pressure. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at coarse-grained resolution. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Many biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. ![]()
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