Thermodynamically reversible paths of the first fusion intermediate reveal an important role for membrane anchors of fusion proteins
Open accessAbstract
Significance: The isolated transmembrane domains (TMDs) of fusion proteins such as SNARE molecules drastically lower the free energy of both the stalk barrier and metastable stalk, which is not trivially explained by molecular shape arguments. The here-demonstrated methodology may have far-reaching applications in the fields of medicine and pharmacology because it enables screening and rational design of novel fusion inhibitors and accelerators.
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Fusogenic proteins, most notably SNAREs, are key drivers of membrane fusion because by pulling membranes together to under 1 nm they reduce lipid hydration and lower the hydration-repulsion energy barrier.
“Fusogenic proteins-most notably SNAREs-are widely recognized as key drivers of membrane fusion because by pulling the membranes together to under 1 nm they reduce lipid hydration and thus lower the hydration-repulsion energy barrier 7,13 .”
From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [13]
The section on SNARE transmembrane domains says membrane anchors bring membranes close together and thereby help lower fusion barriers. But the paper models SNARE-associated membranes at 1.2 nm, not under 1 nm, and says SNARE complexes must overcome hydration repulsion at short distances; it does not say that pulling membranes together lowers that repulsion. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe 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 [13]
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Experimental — accuracy not yet measuredPrevious 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 [13]
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 [13]
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Research works printed but not linked: 1
- Berendsen HJC (2007) Simulating the Physical World (Cambridge Univ Press, Cambridge, UK), pp 211-248.
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Marrink, S. J., Monticelli, L., Melo, M. N., Alessandri, R., Tieleman, D. P., & Souza, P. C. T. (2023) · WIREs Computational Molecular Science · doi:10.1002/wcms.1620 · Cited by 255 · see citing works
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., Risselada, H. J., & Müller, M.
- Affiliations
- University of Göttingen (DE)
- Leiden University (NL)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-01-30
- Volume
- 116
- Issue
- 7
- Pages
- 2571-2576
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6377489
- OpenAlex
- W2913093697
- Cited by
- 81
- References
- 0
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 8 · 2023: 13 · 2022: 10 · 2021: 11 · 2020: 14 · 2019: 7
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (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 › Molecular Biology › Protein Structure and Dynamics
- Keywords
- membrane fusion, minimum free energy path, transmembrane domain, SNARE proteins, hydrophobic mismatch, membrane thinning, membrane curvature, phosphatidylethanolamine, hydration repulsion, membrane anchor
- MeSH terms
- Lipid Bilayers, Membrane Fusion, Thermodynamics, SNARE Proteins, Molecular Dynamics Simulation, Hydrophobic and Hydrophilic Interactions
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