Solvent-Exposed Tails as Prestalk Transition States for Membrane Fusion at Low Hydration
Open accessAbstract
Membrane fusion is a key step in intracellular trafficking and viral infection. The underlying molecular mechanism is poorly understood. We have used molecular dynamics simulations in conjunction with a coarse grained model to study early metastable and transition states during the fusion of two planar palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayers separated by five waters per lipid in the cis leaflets at zero tension. This system mimics the contact area between two vesicles with large diameters compared to the membrane thickness at conditions where fusion may start in the core of the contact area. At elevated temperatures, the two proximal leaflets become connected via multiple lipid molecules and form a stalklike structure. At room temperature, this structure has a free energy of 3k(B)T and is separated from the unconnected state by a significant free energy barrier of 20k(B)T. Stalk formation is initiated by the establishment of a localized hydrophobic contact between the bilayers. This contact is either formed by two partially splayed lipids or a single fully splayed one leading to the formation of a (metastable) splayed lipid bond intermediate. These findings indicate that, for low hydration, early membrane fusion kinetics is not determined by the stalk energy but by the energy of prestalk transition states involving solvent-exposed lipid tails.
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The analysis employs biased molecular-dynamics simulations building on pioneering work on splayed lipids and fusion stalks, and is motivated by the earlier finding that pronounced interfacial dissipation observed between sliding bilayers under transmembrane electric fields arises from spontaneous stalk formation.
“Our analysis employs biased molecular-dynamics simulations building on pioneering work on splayed lipids and fusion stalks 10,13,14,18,32,33 , and is motivated by our earlier finding that the pronounced interfacial dissipation observed between sliding bilayers under transmembrane electric fields arises from spontaneous stalk formation 9 .”
From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [14]
Intermembrane splayed lipids are thought to template the reorientation of surrounding lipids, promoting formation of the stalk, a nanometric lipid bridge connecting the two proximal monolayers.
“Such intermembrane splayed lipids are thought to template the reorientation of surrounding lipids, promoting formation of the next intermediate, the stalk: a nanometric lipid bridge connecting the two proximal monolayers [14][15][16][17] .”
From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [14]
Pulling membranes together greatly increases the likelihood that lipids adopt the splayed state, in which one acyl chain inserts into the opposing membrane.
“This greatly increase the likelihood that lipids adopt the splayed state, in which one acyl chain inserts into the opposing membrane-an energetically costly early fusion intermediate 14 .”
From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [14]
A consistent conclusion from molecular dynamics simulations based on lipid-only systems is that fusogenic proteins are indispensable because they facilitate the otherwise unfavorable intermediates of splayed lipids, stalks, and fusion pores.
“A consistent conclusion is that fusogenic proteins are indispensable because they facilitate the otherwise unfavorable intermediates of splayed lipids, stalks, and fusion pores.”
From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [14]
Previous cornerstone studies established that the splayed state formation is an essential precursor to stalk formation.
“Previous cornerstone studies established that the splayed state formation, as in Fig. 1, and also Fig. 3A, is an essential precursor to stalk formation 13,14,18 .”
From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [14]
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Cites
Molecular anatomy of a trafficking organelle
Takamori, S., Holt, M., Stenius, K., Lemke, E. A., Grønborg, M., Riedel, D., Urlaub, H., Schenck, S., Brügger, B., Ringler, P., et al. (2006) · Cell · doi:10.1016/j.cell.2006.10.030 · Cited by 2,373 · see citing works
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Research works printed but not linked: 3
- [33]Murata, M.; Sugahara, Y.; Takahashi, S.; Ohnishi, S. J. Biochem. 1987 , 102 , 957-962.
- [34]Zellmer, S.; Cevc, G.; Risse, P. Biochim. Biophys. Acta 1994 , 1196 , 101-113.
- [35]Ohta-Iino, S.; Pasenkiewicz-Gierula, M.; Takaoka, Y.; Miyagawa, H; Kitamura, K Biophys. J. 2001 , 81 , 217-224.
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Fusion of lipid membranes: an alternative pathway
Jin, D., Li, Z., Roke, S., & Klein, J. (2026) · doi:10.64898/2026.02.19.706911
- Authors
- Smirnova, Y. G., Marrink, S.-J., Lipowsky, R., & Knecht, V.
- Affiliations
- University of Groningen (NL)
- Corresponding author
- Knecht, Volker
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-04-22
- Volume
- 132
- Issue
- 19
- Pages
- 6710-6718
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2154142515
- Cited by
- 149
- References
- 1
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 7 · 2023: 7 · 2022: 7 · 2021: 11 · 2020: 12 · 2019: 10 · 2018: 5 · 2017: 9 · 2016: 11 · 2015: 6 · 2014: 14 · 2013: 14 · 2012: 16
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- membrane fusion, low hydration, POPC bilayer, hydrophobic interactions, activation barrier, fusion kinetics, coarse-grained lipid model, viral fusion, intracellular trafficking
- MeSH terms
- Kinetics, Lipid Bilayers, Membrane Fusion, Molecular Conformation, Phosphatidylcholines, Solvents, Thermodynamics, Molecular Dynamics Simulation
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