CoChat
Sign Up
Cited by 98Lipid Membrane Structure and BehaviorCellular transport and secretionLipid metabolism and biosynthesis

Free energies of membrane stalk formation from a lipidomics perspective

Open access
Poojari, Chetan S., Scherer, Katharina C., Hub, Jochen S.·2021·Nature Communications
DOI 10.1038/s41467-021-26924-2PMC PMC8593120
Open this paper in CoChat — free accountOpen PDF

Abstract

Many biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at coarse-grained resolution. The method reveals that the inner leaflet of a typical plasma membrane is far more fusogenic than the outer leaflet, which is likely an adaptation to evolutionary pressure. To rationalize these findings by the distinct lipid compositions, we computed ~200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. In summary, the simulations reveal a drastic influence of the lipid composition on stalk formation and a comprehensive fusogenicity map of many biologically relevant lipid classes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-021-26924-2

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [10]

    Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Electroporation of opposing membranes promotes membrane fusion via formation of an intermembrane splayed lipid and peripore stalk, without any protein involvement.

    “Using biased molecular dynamics simulations to carry out extensive potential-of-mean-force calculations 10 , we show how electroporation of opposing membranes promotes membrane fusion via formation of an intermembrane splayed lipid and peripore stalk, without any protein involvement.”

    From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [10]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

No references could be resolved yet.

Research works printed but not linked: 44

  1. [1]van Meer G Voelker DR Feigenson GW Membrane lipids: where they are and how they behave Nat. Rev. Mol. Cell Biol. 2008 9 112 124 18216768 PMC2642958
  2. [2]Shevchenko A Simons K Lipidomics: coming to grips with lipid diversity Nat. Rev. Mol. Cell Biol. 2010 11 593 598 20606693
  3. [3]Op Den Kap JAF Lipid asymmetry in membranes Ann. Rev. Biochem. 1979 48 47 71 382989
  4. [4]Lorent JH Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape Nat. Chem. Biol. 2020 16 644 652 32367017 PMC7246138
  5. [5]Jahn R Lang T Südhof TC Membrane fusion Cell 2003 112 519 533 12600315
  6. [6]Harrison SC Viral membrane fusion Nat. Struct. Mol. Biol. 2008 15 690 698 18596815 PMC2517140
  7. [7]Kielian M Rey FA Virus membrane-fusion proteins: more than one way to make a hairpin Nat. Rev. Microbiol 2006 4 67 76 16357862 PMC7097298
  8. [8]Wickner W Schekman R Membrane fusion Nat. Struct. Mol. Biol. 2008 15 658 664 18618939 PMC2488960
  9. [9]Markin VS Kozlov MM Borovjagin VL On the theory of membrane fusion. The stalk mechanism Gen. Physiol. Biophys. 1984 3 361 377 6510702
  10. [10]Chernomordik LV Kozlov MM Mechanics of membrane fusion Nat. Struct. Mol. Biol. 2008 15 675 683 18596814 PMC2548310
  11. [11]Martens S McMahon HT Mechanisms of membrane fusion: disparate players and common principles Nat. Rev. Mol. Cell Biol. 2008 9 543 556 18496517
  12. [12]Burger KN Greasing membrane fusion and fission machineries Traffic 2000 1 605 613 11208148
  13. [13]Jahn R Südhof TC Membrane fusion and exocytosis Annu. Rev. Biochem. 1999 68 863 911 10872468
  14. [14]Antonny B Vanni S Shindou H Ferreira T From zero to six double bonds: phospholipid unsaturation and organelle function Trends Cell Biol. 2015 25 427 436 25906908
  15. [15]Kozlovsky Y Kozlov MM Stalk model of membrane fusion: solution of energy crisis Biophysical J. 2002 82 882 895 PMC1301897 11806930
  16. [18]Katsov K Müller M Schick M Field theoretic study of bilayer membrane fusion. I. Hemifusion mechanism Biophysical J. 2004 87 3277 3290 PMC1304796 15326031
  17. [19]Smirnova YG Marrink S-J Lipowsky R Knecht V Solvent-exposed tails as prestalk transition states for membrane fusion at low hydration J. Am. Chem. Soc. 2010 132 6710 6718 20411937
  18. [20]Risselada HJ Kutzner C Grubmüller H Caught in the act: visualization of SNARE-mediated fusion events in molecular detail ChemBioChem 2011 12 1049 1055 21433241
  19. [21]Kawamoto S Shinoda W Free energy analysis along the stalk mechanism of membrane fusion Soft Matter 2014 10 3048 24695575
  20. [22]Markvoort, A. J. & Marrink, S. J. Current Topics in Membranes Vol. 68; 259–294 (Elsevier, 2011). 21771503
  21. [24]Risselada HJ Grubmüller H How SNARE molecules mediate membrane fusion: recent insights from molecular simulations Curr. Opin. Struct. Biol. 2012 22 187 196 22365575
  22. [25]Marrink SJ Mark AE The mechanism of vesicle fusion as revealed by molecular dynamics simulations J. Am. Chem. Soc. 2003 125 11144 11145 16220905
  23. [26]Kasson PM Pande VS Control of membrane fusion mechanism by lipid composition: predictions from ensemble molecular dynamics PLoS Comput. Biol. 2007 3 e220 18020701 PMC2077900
  24. [27]Smirnova YG Risselada HJ Müller M Thermodynamically reversible paths of the first fusion intermediate reveal an important role for membrane anchors of fusion proteins Proc. Natl Acad. Sci. USA 2019 116 2571 2576 30700547 PMC6377489
  25. [28]Hub JS Awasthi N Probing a continuous polar defect: a reaction coordinate for pore formation in lipid membranes J. Chem. Theory Comput. 2017 13 2352 2366 28376619
  26. [29]Ting, C. L., Awasthi, N., Müller, M. & Hub, J. S. Metastable prepores in tension-free lipid bilayers. Phys. Rev. Lett. 120, 128103 (2018). 29694074
  27. [30]Kozlovsky Y Efrat A Siegel DA Kozlov MM Stalk phase formation: effects of dehydration and saddle splay modulus Biophysical J. 2004 87 2508 2521 PMC1304670 15454446
  28. [31]Marrink SJ Tieleman DP Perspective on the Martini model Chem. Soc. Rev. 2013 42 6801 23708257
  29. [32]Siegel D Epand R The mechanism of lamellar-to-inverted hexagonal phase transitions in phosphatidylethanolamine: implications for membrane fusion mechanisms Biophysical J. 1997 73 3089 3111 PMC1181213 9414222
  30. [33]Chernomordik LV Kozlov MM Membrane hemifusion: crossing a chasm in two leaps Cell 2005 123 375 382 16269330
  31. [34]Kurniawan J Suga K Kuhl TL Interaction forces and membrane charge tunability: Oleic acid containing membranes in different pH conditions Biochim. et. Biophys. Acta 2017 1859 211 217 27823928
  32. [35]Aeffner S Reusch T Weinhausen B Salditt T Energetics of stalk intermediates in membrane fusion are controlled by lipid composition Proc. Natl Acad. Sci. USA 2012 109 E1609 E1618 22589300 PMC3382523
  33. [36]Risselada HJ Bubnis G Grubmuller H Expansion of the fusion stalk and its implication for biological membrane fusion Proc. Natl Acad. Sci. USA 2014 111 11043 11048 25024174 PMC4121774
  34. [37]Yang S-T Kreutzberger AJ Lee J Kiessling V Tamm LK The role of cholesterol in membrane fusion Chem. Phys. Lipids 2016 199 136 143 27179407 PMC4972649
  35. [38]McIntosh TJ Magid AD Simon SA Cholesterol modifies the short-range repulsive interactions between phosphatidylcholine membranes Biochemistry 1989 28 17 25 2706242
  36. [39]Walter A Yeagle P Siegel D Diacylglycerol and hexadecane increase divalent cation-induced lipid mixing rates between phosphatidylserine large unilamellar vesicles Biophys. J. 1994 66 366 376 8161690 PMC1275704
  37. [40]Basanez G Diacylglycerol and the promotion of lamellar-hexagonal and lamellar-isotropic phase transitions in lipids: implications for membrane fusion Biophys. J. 1996 70 2299 2306 9172753 PMC1225204
  38. [41]Dhiman R Caesar S Thiam AR Schrul B Mechanisms of protein targeting to lipid droplets: a unified cell biological and biophysical perspective Semin. Cell Dev. Biol. 2020 108 4 13 32201131
  39. [42]Fuller N Benatti CR Peter Rand R Curvature and bending constants for phosphatidylserine-containing membranes Biophys. J. 2003 85 1667 1674 12944281 PMC1303340
  40. [43]Awasthi N Hub JS Simulations of pore formation in lipid membranes: reaction coordinates, convergence, hysteresis, and finite-size effects J. Chem. Theory Comput. 2016 12 3261 3269 27254744
  41. [44]Awasthi N Molecular mechanism of polycation-induced pore formation in biomembranes ACS Biomater. Sci. Eng. 2019 5 780 794 33405839
  42. [45]Dhara M Synergistic actions of v-SNARE transmembrane domains and membrane-curvature modifying lipids in neurotransmitter release eLife 2020 9 e55152 32391794 PMC7239655
  43. [47]Marrink SJ Risselada HJ Yefimov S Tieleman DP de Vries AH The MARTINI force field: coarse grained model for biomolecular simulations J. Phys. Chem. B 2007 111 7812 7824 17569554
  44. [48]Hub, J. S., Poojari, C. S. & Scherer, K. C. Simulation systems of: “Free energies of membrane stalk formation from a lipidomics perspective" (Version v1) [Data set]. Zenodo. 10.5281/zenodo.5196036. PMC8593120 34782611 · DOI

Cited by

Sorted by citations

Authors
Poojari, C. S., Scherer, K. C., & Hub, J. S.
Affiliations
Saarland University (DE)
Corresponding author
Hub, Jochen S.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-11-15
Volume
12
Issue
1
Pages
6594-6594
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-26924-2
PMC
PMC8593120
OpenAlex
W3213665403
Cited by
98
References
0
Citations by year
2026: 23 · 2025: 18 · 2024: 28 · 2023: 17 · 2022: 12
FWCI
4.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Publications of the UdS (Saarland University) (cc-by)
Funders
Deutsche Forschungsgemeinschaft (SFB 1027/B7)
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, lipidomics, free energy, lipid composition, fusogenicity, membrane asymmetry, plasma membrane, lipid head groups, lipid tail length, lipid unsaturation, sterols, coarse-grained simulation
MeSH terms
Lipidomics, Biophysics, Cell Membrane, Kinetics, Membrane Fusion, Membranes, Thermodynamics, Entropy, Computational Biology

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review