A quantitative model for membrane fusion based on low-energy intermediates

Abstract

The energetics of a fusion pathway is considered, starting from the contact site where two apposed membranes each locally protrude (as ''nipples'') toward each other. The equilibrium distance between the tips of the two nipples is determined by a balance of physical forces: repulsion caused by hydration and attraction generated by fusion proteins. The energy to create the initial stalk, caused by bending of cis monolayer leaflets, is much less when the stalk forms between nipples rather than parallel flat membranes. The stalk cannot, however, expand by bending deformations alone, because this would necessitate the creation of a hydrophobic void of prohibitively high energy. But small movements of the lipids out of the plane of their monolayers allow transformation of the stalk into a modified stalk. This intermediate, not previously considered, is a low-energy structure that can reconfigure into a fusion pore via an additional intermediate, the prepore. The lipids of this latter structure are oriented as in a fusion pore, but the bilayer is locally compressed. All membrane rearrangements occur in a discrete local region without creation of an extended hemifusion diaphragm. Importantly, all steps of the proposed pathway are energetically feasible.

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

“…3B) (46). In case of DPhPC, the dimples of the trans monolayers seem to be slightly more pronounced than in case of the other lipids, however, compared to stalk structures obtained by theory (11)(12)(13)(14), they are rather weak. For further analysis and to quantify possible changes, we use the contours of maximum electron density contrast to define the four structural The dimensionless ratios of structural parameters display very similar values for all investigated lipids.…”

“…(33). The area under each curve between a given value d w and infinity, λ h P 0 expð−d w ∕ λ h Þ, yields an estimate for the energy (per unit area) required for dehydration up to this point for the particular lipid composition (11). A lower bound for the contact area of two merging bilayers is the cross-sectional area of a stalk, for which we obtain a typical value of A s ¼ πd 2 s ∕4 ¼ 20 nm 2 (see below).…”

“…A persistent problem in membrane biophysics is to determine the precise structure of stalks and the free energy barrier for stalk formation. In a long series of papers (8)(9)(10)(11)(12)(13)(14)(15)(16), this determination has been attempted within the framework of the continuum theory of membrane elasticity (17,18). More recently, with the advent of sufficient computational power, simulations including molecular details have become feasible [e.g.…”

Structures of vesicular stomatitis virus glycoprotein: membrane fusion revisited

“…The activation energy of the fusion process has been estimated to be in the range of 40 kcal/mol [26,70,71], most of which is required by enlargement of the initial fusion pore. For class I and class II fusion proteins, it has been proposed that the energy released during the irreversible fusogenic transition is used to achieve the energetically expensive membrane-fusion reaction [ 50,72,73], and experimental data suggest that in the case of HIV a single env glycoprotein trimer is sufficient for fusion [74].…”

Low pH Stabilizes the Inverted Hexagonal II Phase in Dipalmitoleoylphosphatidylethanolamine Membrane

“…In recent years, a great deal of attention has been given to the liquid-crystalline (L α ) phase/inverted hexagonal II (H II ) phase transition (Figure 1), because it is believed to be vital to understand the membrane fusion and the functions of membrane proteins [1][2][3][4]. The structure and phase properties of various kinds of phosphatidylethanolamine (PE) membrane have been extensively studied by a variety of methods, including differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), X-ray diffraction, Fourier-transform infrared spectroscopy (FTIR), and fluorescence [5][6][7].…”