Field Theoretic Study of Bilayer Membrane Fusion. I. Hemifusion Mechanism

Abstract

Self-consistent field theory is used to determine structural and energetic properties of metastable intermediates and unstable transition states involved in the standard stalk mechanism of bilayer membrane fusion. A microscopic model of flexible amphiphilic chains dissolved in hydrophilic solvent is employed to describe these self-assembled structures. We find that the barrier to formation of the initial stalk is much smaller than previously estimated by phenomenological theories. Therefore its creation it is not the rate-limiting process. The relevant barrier is associated with the rather limited radial expansion of the stalk into a hemifusion diaphragm. It is strongly affected by the architecture of the amphiphile, decreasing as the effective spontaneous curvature of the amphiphile is made more negative. It is also reduced when the tension is increased. At high tension the fusion pore, created when a hole forms in the hemifusion diaphragm, expands without bound. At very low membrane tension, small fusion pores can be trapped in a flickering metastable state. Successful fusion is severely limited by the architecture of the lipids. If the effective spontaneous curvature is not sufficiently negative, fusion does not occur because metastable stalks, whose existence is a seemingly necessary prerequisite, do not form at all. However if the spontaneous curvature is too negative, stalks are so stable that fusion does not occur because the system is unstable either to a phase of stable radial stalks, or to an inverted-hexagonal phase induced by stable linear stalks. Our results on the architecture and tension needed for successful fusion are summarized in a phase diagram.

Energetics of stalk intermediates in membrane fusion are controlled by lipid composition

“…In simulations of bilayer fusion, two parallel patches of lipid bilayers are usually "prepared" in dehydrated conditions; i.e., at a fixed number of water molecules per lipid molecule well below the one in fully hydrated conditions. Therefore, also here, the free energy cost for stalk formation of 3-15 k B T obtained by different simulation methods (46,61,67) does not include the energy required to establish close bilayer contact, and this hydration barrier based on our results would by far exceed the free energy difference of 3-15 k B T for the last step from dehydrated bilayers to a stalk. Thus, we believe the present results call for a revision of the current curvature-centered view, and suggest to reinforce work on hydration effects in stalk formation and membrane fusion.…”

“…It is debated to what extent this approach and truncating the series expansion of bending energy after quadratic terms in c 1 , c 2 are justified and sufficient in case of strongly bent monolayers such as in membrane fusion intermediate structures (12,13,46,57,61). In addition, as a general concern, it may be doubted if neglecting molecular details is a valid approach on these length scales (57).…”

Negatively Charged Lipids as a Potential Target for New Amphiphilic Aminoglycoside Antibiotics

“…Such an effect could contribute to promote the subsequent increase in the area of one monolayer with respect to the other (61). Membrane reorganization and lipid segregation could result ultimately in membrane permeabilization and membrane reorganization with hemifusion and/or stalk intermediates (62)(63)(64).…”

Minimum free energy paths for a nanoparticle crossing the lipid membrane

“…13, 18 and 26. We note that the model used in this work is in the same spirit as that used in the work of Katsov et al in their study of membrane fusion in lipid bilayers. 40,41 The final expression for the grand potential is:…”