Energetics of Vesicle Fusion Intermediates: Comparison of Calculations with Observed Effects of Osmotic and Curvature Stresses

Malinin, Vladimir; Lentz, Barry R.

doi:10.1016/s0006-3495(04)74346-5

Cited by 88 publications

(139 citation statements)

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“…The influence of lipid composition on membrane fusion intermediates has received an extensive theoretical treatment from a continuum-mechanics perspective [10,[23][24][25]29,32,67]. Our simulations provide an alternative approach by using molecular dynamics to treat lipid bilayers as discrete rather than continuous entities.…”

Section: Discussionmentioning

confidence: 99%

Control of membrane fusion mechanism by lipid composition: predictions from ensemble molecular dynamics

Kasson

Pande

2005

PLoS Comput Biol

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Membrane fusion is critical to biological processes such as viral infection, endocrine hormone secretion, and neurotransmission, yet the precise mechanistic details of the fusion process remain unknown. Current experimental and computational model systems approximate the complex physiological membrane environment for fusion using one or a few protein and lipid species. Here, we report results of a computational model system for fusion in which the ratio of lipid components was systematically varied, using thousands of simulations of up to a microsecond in length to predict the effects of lipid composition on both fusion kinetics and mechanism. In our simulations, increased phosphatidylcholine content in vesicles causes increased activation energies for formation of the initial stalk-like intermediate for fusion and of hemifusion intermediates, in accordance with previous continuum-mechanics theoretical treatments. We also use our large simulation dataset to quantitatively compare the mechanism by which vesicles fuse at different lipid compositions, showing a significant difference in fusion kinetics and mechanism at different compositions simulated. As physiological membranes have different compositions in the inner and outer leaflets, we examine the effect of such asymmetry, as well as the effect of membrane curvature on fusion. These predicted effects of lipid composition on fusion mechanism both underscore the way in which experimental model system construction may affect the observed mechanism of fusion and illustrate a potential mechanism for cellular regulation of the fusion process by altering membrane composition.

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Section: Discussionmentioning

confidence: 99%

Control of membrane fusion mechanism by lipid composition: predictions from ensemble molecular dynamics

Kasson

Pande

2005

PLoS Comput Biol

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“…Lentz (2007) 15 summarized these mechanisms as follows: increasing surface tension, altering structure and dielectric properties of bulk water, altering the bilayer molecular order at the point of contact, promoting volume exclusion-induced aggregation and dehydration, inducing a non-bilayer structure, inducing bilayer-destabilizing phase separation, and producing compression followed by expansive osmotic stress on the membrane vesicles upon dilution, leading the contained impurities to disrupt the membrane. To understand the fusion process, the "stalk model" has been developed over the years to explain the merging phenomenon [16][17][18] . In this model, at least two intermediates have been reported.…”

Section: Introductionmentioning

confidence: 99%

Effect of Hydration and Packing Order on Large Unilamellar Vesicle Fusion: The Role of Cholesterol

Cuevas

Valle

Aguilar

2017

J. Chil. Chem. Soc.

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Several studies examining vesicle fusion have been reported in last decades and have established a number of factors favoring the process of vesicle fusion. To determine whether variations to the physicochemical properties of the membrane affect the process of vesicle fusion, we worked with binary and ternary mixtures of large unilamellar vesicles (LUVs). The selected binary models were dioleoyl phosphocholine-cholesterol (DOPC-chol) and disteraroyl phosphocholine-cholesterol (DSPC-chol), and the tertiary mixtures were phosphatidylcholine-phsophatidylethanolamine-cholesterol (PC-PE-Chol); phosphatidylcholine-sphingomyelincholesterol (PC-SM-Chol); and phosphatidylcholine-phosphatidylserine-cholesterol (PC-PS-Chol). For all these models, the effect of cholesterol content on the lamella physicochemical properties was determined using 1,6-diphenyl-1,3,5-hexatriene (DPH) anisotropy, generalized polarization of 2-dimethylamino-6-lauroylnaphthalene (Laurdan), and DPH fluorescence lifetime. To determine whether fusion of these vesicles varied according to lipid composition, the % mixing content and the % leakage were determined. Examining membrane incorporation using fluorescence steady-state and time-resolved probe assays in the models indicated that cholesterol content affected packing order and lamellar hydration. In most of the models, nonmonotonic variations were observed for these parameters, and these variations could be interpreted as increases in the proportion of ordered microdomains. When the proportion of these domains is higher, the packing order increases, and the lamellar water decrease. Similarly, the % mixing, which was assessed as a fusion parameter, also exhibited nonmonotonic behavior, indicating that the fusion process is enhanced at these concentrations of cholesterol. However, DSPC vesicles do not merge, so more than the presence of microdomains is required to stabilize fusion.

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“…Such an extreme curvature approaches the upper bound of membrane curvature that fusion proteins, such as synaptotagmin, can generate when being overexpressed on the membrane (30). The exaggerated curvature stress of the here-modeled fusion site should approach the lower bound of the in vivo expansion barrier (31,32). In addition, we explored the effect of phosphatidylethanolamine (PE) lipids and cholesterol, the two abundant "fusogens" in the plasma membrane, on the expansion of the metastable stalk.…”

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confidence: 99%

Expansion of the fusion stalk and its implication for biological membrane fusion

Risselada

Bubnis

Grubmüller

2014

Proc. Natl. Acad. Sci. U.S.A.

104

115

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Over the past 20 years, it has been widely accepted that membrane fusion proceeds via a hemifusion step before opening of the productive fusion pore. An initial hourglass-shaped lipid structure, the fusion stalk, is formed between the adjacent membrane leaflets (cis leaflets). It remains controversial if and how fusion proteins drive the subsequent transition (expansion) of the stalk into a fusion pore. Here, we propose a comprehensive and consistent thermodynamic understanding in terms of the underlying free-energy landscape of stalk expansion. We illustrate how the underlying free energy landscape of stalk expansion and the concomitant pathway is altered by subtle differences in membrane environment, such as leaflet composition, asymmetry, and flexibility. Nonleaky stalk expansion (stalk widening) requires the formation of a critical trans-leaflet contact. The fusion machinery can mechanically enforce trans-leaflet contact formation either by directly enforcing the trans-leaflets in close proximity, or by (electrostatically) condensing the area of the cis leaflets. The rate of these fast fusion reactions may not be primarily limited by the energetics but by the forces that the fusion proteins are able to exert.embrane fusion is a fundamental process in cell biophysics, being involved in viral infection, endo-and exocytosis, and fertilization. The textbook example of membrane fusion comprises three experimentally observed metastable lipidic structures-namely, the rhombohedral stalk (1, 2), the hemifusion diaphragm (HD) (3-5), and the toroidal fusion pore (6). These structures represent (local) free energy minima that are connected via transient states (free energy barriers) within the fusion pathway. How the stalk transitions (expands) into the fusion pore remains controversial (7-9). Different pathways have been proposed based on experimental observations (3, 5, 10-13), molecular simulations (8,9,(14)(15)(16)(17)(18)(19)(20), continuum elastic models (15,21,22), and self-consistent field theory (23,24).Arguably, the best-studied fusion reactions are the ones mediated by influenza hemagglutinin and soluble N-ethylmaleimidesensitive-factor attachment receptor (SNARE) molecules. Hemagglutinin-mediated fusion displays an unusual sensitivity toward point mutations in its amphiphilic fusion peptide. Here, even single point mutations can selectively trap the fusion reaction in a hemifused state (25). Hemagglutinin therefore very likely plays an active, essential role in the subsequent evolution of hemifusion intermediates (20). In contrast, it remains unclear if SNARE molecules play a role therein. SNARE molecules subject force on the membrane via the ends of the transmembrane domains (TMDs) (26). The X-ray-resolved structure of the postfusion neuronal SNARE complex suggests that TMDs come together during the fusion reaction, and may actively drive fusion up to the expansion of the fusion pore (27). However, in vitro and in vivo experiments, where the TMD was either replaced by a lipid anchor or partly truncated, pro...

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Energetics of Vesicle Fusion Intermediates: Comparison of Calculations with Observed Effects of Osmotic and Curvature Stresses

Cited by 88 publications

References 56 publications

Control of membrane fusion mechanism by lipid composition: predictions from ensemble molecular dynamics

Control of membrane fusion mechanism by lipid composition: predictions from ensemble molecular dynamics

Effect of Hydration and Packing Order on Large Unilamellar Vesicle Fusion: The Role of Cholesterol

Expansion of the fusion stalk and its implication for biological membrane fusion

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