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

Abstract

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.

Activation energy and force fields during topological transitions of fluid lipid vesicles

“…At this moment the critical state is reached, and, from then onwards, the neck tends to spontaneously expand under the action of its own elasticity. These intermediate configurations are reminiscent of those found in experiments 40 and MD simulations 22,23,28 , i.e. pre-fusion states, stalks, hemifusions, and fusion pores.…”

“…The most commonly used techniques for in silico studies of topological transitions to date are coarse-grained molecular dynamics (MD) and dissipative particle dynamics (DPD) [18][19][20][21][22][23][24][25][26][27][28] . These computer simulations, which take into account the molecular details of lipid bilayers, allow monitoring in time morphological changes of small liposomes 29 .…”

The local variation of the Gaussian modulus enables different pathways for fluid lipid vesicle fusion

“…The insertion of a HA fusion peptide releases about 13 k B T , thus the action of three neighboring HA trimers is thought to generate enough energy to perturb the bilayer and overcome the dehydration barrier that keeps the two membranes apart [50], a task also accomplished by increasing the protrusion of lipid tails [51]. Thus, this energy released upon insertion can be used to move from the zeroth stage of fusion [38] to the following one. Once in close contact, fusion could proceed thermally due to the presence of HA.…”

High curvature promotes fusion of lipid membranes: Predictions from continuum elastic theory

“…It is generally accepted that the stalk constitutes a metastable minimum in the free energy landscape and that a significant energy barrier in the fusion reaction, E stalk , with a typical magnitude of several dozens of k B T has to be overcome to reach it ( 12 , 13 , 14 , 15 ). Computer simulations indicate that apart from lipid deformations, also hydration forces play an important role in this barrier ( 16 ). At this point in the reaction, the lipids in the outer (proximal) monolayers mix, which can be used experimentally to identify this state.…”