How does curvature affect the free-energy barrier of stalk formation? Small vesicles vs apposing, planar membranes

Using molecular simulations of POPC lipids in conjunction with the calculation of the Minimum Free-Energy Path (MFEP), we study the effect of strong membrane curvature on the formation of the first fusion intermediate-the stalk between a vesicle and its periodic image. We find that the thermodynamic stability of this hourglass-shaped, hydrophobic connection between two vesicles is largely increased by the strong curvature of small vesicles, whereas the intrinsic barrier to form a stalk, i.e., associated with dimple formation and lipid tails protrusions, is similar to the case of two, apposing, planar membranes. A significant reduction of the barrier of stalk formation, however, stems from the lower dehydration free energy that is required to bring highly curved vesicle into a distance, at which stalk formation may occur, compared to the case of apposing, planar membranes.