Free energies of stalk formation in the lipidomics era

Abstract

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 near-atomic resolution. The new 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 ~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.

Lipid Droplets Embedded in a Model Cell Membrane Create a Phospholipid Diffusion Barrier

“…Because the cone-shaped PE lipids favor negative curvature, they may accumulate along the pore rim and, thereby, stabilize the stalk intermediate. [31,32] Notably, PLDs and LD required the same conditions for successful insertion into the bilayer.…”