Free energies of membrane stalk formation from a lipidomics perspective

Fusion of cellular membranes begins with the formation of a stalk. Here, the authors develop a computationally efficient method for coarse-grained simulations of stalk formation and apply this approach to comprehensively analyse how stalk formation is influenced by the membrane lipid composition. Many biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at coarse-grained resolution. 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. To rationalize these findings by the distinct lipid compositions, we computed similar to 200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. 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.

Automated summary

The authors developed a computationally efficient method to simulate stalk formation and analyzed how membrane lipid composition influences this process. They found that the inner leaflet of a typical plasma membrane is more fusogenic than the outer leaflet, possibly as an adaptation to evolutionary pressure.