Field theoretic study of bilayer membrane fusion: I. Hemifusion mechanism

TL;DR

This study uses self-consistent field theory to analyze the structural and energetic aspects of membrane fusion, revealing that the initial stalk formation is easier than previously thought and that membrane architecture and tension critically influence fusion success.

Contribution

It provides a microscopic, quantitative analysis of the fusion process, highlighting the roles of amphiphile architecture and tension, and challenges prior phenomenological estimates of energy barriers.

Findings

The barrier to stalk formation is smaller than previously estimated.

Fusion success depends on amphiphile spontaneous curvature and membrane tension.

A phase diagram summarizes conditions for successful fusion.

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 barrier which is relevant 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.