Formation of pores in membranes asymmetrical in lipid composition of monolayers

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Abstract

Plasma membranes perform a barrier function in cells, preventing free exchange between the external environment and the intracellular space. The permeability of the plasma cell membrane can be artificially increased by forming through pores. The outer and inner monolayers of the plasma membranes of cells typically have different lipid composition. Currently, a theoretical description of the poration of membranes with monolayers symmetrical in lipid composition has been developed. In the present work, we consider the process of pore formation in membranes, whose monolayers have different spontaneous curvatures due to the difference in their lipid composition. In the framework of the theory of lipid membrane elasticity and considering hydrophobic interactions, the dependence of the pore energy on the radius is calculated. It is shown that the dependences of pore energy on radius are qualitatively different in asymmetric and symmetrical membranes. The pore energy in the asymmetric membrane differs from the pore energy in the symmetric membrane at any values of the spontaneous curvature of the monolayers of the symmetric membrane. Thus, it is incorrect to predict the course of the pore formation in an asymmetric membrane on the basis of data obtained on symmetric membranes; the asymmetry of lipid composition (spontaneous curvature) of monolayers should be explicitly taken into account.

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About the authors

A. A. Simonov

Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences

Email: akimov_sergey@mail.ru
Russian Federation, Moscow, 119071

S. A. Akimov

Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences

Author for correspondence.
Email: akimov_sergey@mail.ru
Russian Federation, Moscow, 119071

References

  1. Puc M., Flisar K., Reberšek S., Miklavčič D. 2001. Electroporator for in vitro cell permeabilization. Radiol. Oncol. 35, 203–207.
  2. Mir L.M. 2001. Therapeutic perspectives of in vivo cell electropermeabilization. Bioelectrochemistry. 53, 1–10.
  3. Potter H. 1989. Molecular genetic applications of electroporation. In Electroporation and electrofusion in cell biology. Eds. Neumann E., Sowers A.E., Jordan C.A. New York and London: Plenum Press, 331–342.
  4. Pavlov R.V., Akimov S.A., Dashinimaev E.B., Bashkirov P.V. 2024. Boosting lipofection efficiency through enhanced membrane fusion mechanisms. Int. J. Mol. Sci. 25, 13540.
  5. Pérez-Peinado C., Dias S.A., Domingues M.M., Benfield A.H., Freire J.M., Rádis-Baptista G., Gaspar D., Castanho M.A.R.B., Craik D.J., Henriques S.T., Veiga A.S., Andreu D. 2018. Mechanisms of bacterial membrane permeabilization by crotalicidin (Ctn) and its fragment Ctn (15–34), antimicrobial peptides from rattlesnake venom. J. Biol. Chem. 293, 1536–1549.
  6. Shipunova V.O., Komedchikova E.N., Kotelnikova P.A., Nikitin M.P., Deyev S.M. 2023. Targeted two-step delivery of oncotheranostic nano-PLGA for HER2-positive tumor imaging and therapy in vivo: Improved effectiveness compared to one-step strategy. Pharmaceutics. 15, 833.
  7. Novoselova M., Chernyshev V.S., Schulga A., Konovalova E.V., Chuprov-Netochin R.N., Abakumova T.O., German S., Shipunova V.O., Mokrousov M.D., Prikhozhdenko E., Bratashov D.N., Bogorodskiy A., Grishin O., Kosolobov S.S., Khlebtsov B.N., Inozemtseva O., Zatsepin T.S., Deyev S.M., Gorin D.A. 2022. Effect of surface modification of multifunctional nanocomposite drug delivery carriers with DARPin on their biodistribution in vitro and in vivo. ACS Appl. Bio Materials. 5, 2976–2989.
  8. Rathinakumar R., Wimley W.C. 2008. Biomolecular engineering by combinatorial design and high-throughput screening: small, soluble peptides that permeabilize membranes. J. Am. Chem. Soc. 130, 9849–9858.
  9. Guha S., Ghimire J., Wu E., Wimley W.C. 2019. Mechanistic landscape of membrane-permeabilizing peptides. Chem. Rev. 119, 6040–6085.
  10. Singer S.J., Nicolson G.L. 1972. The fluid mosaic model of the structure of cell membranes: Cell membranes are viewed as two-dimensional solutions of oriented globular proteins and lipids. Science. 175, 720–731.
  11. Ingólfsson H.I., Melo M.N., Van Eerden F.J., Arnarez C., Lopez C.A., Wassenaar T.A., Periole X., de Vries A.H., Tieleman D.P., Marrink S.J. 2014. Lipid organization of the plasma membrane. J. Am. Chem. Soc. 136, 14554–14559.
  12. Ingólfsson H.I., Carpenter T.S., Bhatia H., Bremer P.T., Marrink S.J., Lightstone F.C. 2017. Computational lipidomics of the neuronal plasma membrane. Biophys. J. 113, 2271–2280.
  13. Verkleij A.J., Zwaal R.F., Roelofsen B., Comfurius P., Kastelijn D., van Deenen L.L. 1973. The asymmetric distribution of phospholipids in the human red cell membrane. A combined study using phospholipases and freeze-etch electron microscopy. Biochim. Biophys. Acta 323, 178–193.
  14. Bretscher M.S. 1972. Asymmetrical lipid bilayer structure for biological membranes. Nature New Biol. 236, 11–12.
  15. Hsieh M.K., Klauda J.B. 2021. Leaflet asymmetry modeling in the lipid composition of Escherichia coli cytoplasmic membranes. J. Phys. Chem. B 126, 184–196.
  16. Parvez F., Alam J.M., Dohra H., Yamazaki M. 2018. Elementary processes of antimicrobial peptide PGLa-induced pore formation in lipid bilayers. Biochim. Biophys. Acta. 1860, 2262–2271.
  17. Pfeffermann J., Eicher B., Boytsov D., Hannesschlaeger C., Galimzyanov T.R., Glasnov T.N., Pabst G., Akimov S.A., Pohl P. 2021. Photoswitching of model ion channels in lipid bilayers. J. Photochem. Photobiol. B 224, 112320.
  18. Huang Y. 2022. Assembly methods for asymmetric lipid and polymer-lipid vesicles. Emerg. Top. Life Sci. 6, 609–617.
  19. London E. 2019. Membrane structure-function insights from asymmetric lipid vesicles. Acc. Chem. Res. 52, 2382–2391.
  20. Kamiya K., Kawano R., Osaki T., Akiyoshi K., Takeuchi S. 2016. Cell-sized asymmetric lipid vesicles facilitate the investigation of asymmetric membranes. Nat. Chem. 8, 881–889.
  21. Kakuda S., Li B., London E. 2021. Preparation and utility of asymmetric lipid vesicles for studies of perfringolysin O-lipid interactions. Meth. Enzymol. 649, 253–276.
  22. Kirby C., Green C. 1977. Transmembrane migration ('flip-flop') of cholesterol in erythrocyte membranes. Biochem. J. 168, 575–577.
  23. Hasan M., Karal M.A.S., Levadnyy V., Yamazaki M. 2018. Mechanism of initial stage of pore formation induced by antimicrobial peptide magainin 2. Langmuir. 34, 3349–3362.
  24. Карпунин Д.В., Акимов С.А., Фролов В.А. 2005. Формирование пор в плоских липидных мембранах, содержащих лизолипиды и холестерин. Биол. мембраны. 22, 429–432.
  25. Akimov S.A., Volynsky P.E., Galimzyanov T.R., Kuzmin P.I., Pavlov K.V., Batishchev O.V. 2017. Pore formation in lipid membrane II: Energy landscape under external stress. Sci. Rep. 7, 12509.
  26. Дерягин Б.В., Гутоп Ю.В. 1962. Теория разрушения (прорыва) свободных пленок. Коллоидн. журн. 24, 431–437.
  27. Акимов С.А., Александрова В.В., Галимзянов Т.Р., Башкиров П.В., Батищев О.В. 2017. Механизм формирования пор в мембранах из стеароилолеоилфосфатидилхолина под действием латерального натяжения. Биол. мембраны. 34, 270–283.
  28. Abidor I.G., Arakelyan V.B., Chernomordik L.V., Chizmadzhev Y.A., Pastushenko V.F., Tarasevich M.P. 1979. Electric breakdown of bilayer lipid membranes: I. The main experimental facts and their qualitative discussion. J. Electroanal. Chem. Interfacial Electrochem. 104, 37–52.
  29. Marcelja S. 1977. Structural contribution to solute-solute interaction. Croat. Chem. Acta. 49, 347–357.
  30. Israelachvili J., Pashley R. 1982. The hydrophobic interaction is long range, decaying exponentially with distance. Nature. 300, 341–342.
  31. Hamm M., Kozlov M.M. 2000. Elastic energy of tilt and bending of fluid membranes. Eur. Phys. J. E. 3, 323–335.
  32. Molotkovsky R.J., Alexandrova V.V., Galimzyanov T.R., Jiménez-Munguía I., Pavlov K.V., Batishchev O.V., Akimov S.A. 2018. Lateral membrane heterogeneity regulates viral-induced membrane fusion during HIV entry. Int. J. Mol. Sci. 19, 1483.
  33. Akimov S.A., Polynkin M.A., Jiménez-Munguía I., Pavlov K.V., Batishchev O.V. 2018. Phosphatidylcholine membrane fusion is pH-dependent. Int. J. Mol. Sci. 19, 1358.
  34. Leikin S., Kozlov M.M., Fuller N.L., Rand R.P. 1996. Measured effects of diacylglycerol on structural and elastic properties of phospholipid membranes. Biophys. J. 71, 2623–2632.
  35. Kondrashov O.V., Galimzyanov T.R., Pavlov K.V., Kotova E.A., Antonenko Y.N., Akimov S.A. 2018. Membrane elastic deformations modulate gramicidin A transbilayer dimerization and lateral clustering. Biophys. J. 115, 478–493.
  36. Nagle J.F., Wilkinson D.A. 1978. Lecithin bilayers. Density measurement and molecular interactions. Biophys. J. 23, 159–175.
  37. Rawicz W., Olbrich K.C., McIntosh T., Needham D., Evans E. 2000. Effect of chain length and unsaturation on elasticity of lipid bilayers. Biophys. J. 79, 328–339.
  38. Kozlovsky Y., Efrat A., Siegel D.A., Kozlov M.M. 2004. Stalk phase formation: Effects of dehydration and saddle splay modulus. Biophys. J. 87, 2508–2521.
  39. Akimov S.A., Volynsky P.E., Galimzyanov T.R., Kuzmin P.I., Pavlov K.V., Batishchev O.V. 2017. Pore formation in lipid membrane I: Continuous reversible trajectory from intact bilayer through hydrophobic defect to transversal pore. Sci. Rep. 7, 12152.
  40. Kollmitzer B., Heftberger P., Rappolt M., Pabst G. 2013. Monolayer spontaneous curvature of raft-forming membrane lipids. Soft Matter. 9, 10877–10884.
  41. Fuller N., Rand R.P. 2001. The influence of lysolipids on the spontaneous curvature and bending elasticity of phospholipid membranes. Biophys. J. 81, 243–254.
  42. Maer A.M., Rusinova R., Providence L.L., Ingólfsson H.I., Collingwood S.A., Lundbæk J.A., Andersen O.S. 2022. Regulation of gramicidin channel function solely by changes in lipid intrinsic curvature. Front. Physiol. 13, 836789.
  43. Horner A., Akimov S.A., Pohl P. 2013. Long and short lipid molecules experience the same interleaflet drag in lipid bilayers. Phys. Rev. Lett. 110, 268101.

Supplementary files

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2. Fig. 1. Energy of a film with a pore of radius R in the Deryagin–Gutop model. The graph is constructed under the assumption that a lateral tension of Σ = 2 mN/m and a linear tension of the pore edge of γ = 10 pN are applied to the film.

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3. Fig. 2. Hydrophobic defect in a membrane asymmetric in the composition of monolayers. A schematic cross-section of the membrane with a defect is shown by a plane passing through the axis of rotational symmetry of the system.

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4. Fig. 3. Deformations of the membrane near the hydrophobic cylinder. The section of the membrane with a defect is shown schematically by a plane passing through the axis of rotational symmetry of the system. The radius of the defect is R, the length of the hydrophobic cylinder is L. For a given radius R of the hydrophobic cylinder, its length L is determined from the condition of minimal total (hydrophobic and elastic) energy.

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5. Fig. 4. Dependence of the pore energy on the radius in a symmetric membrane. The spontaneous curvature of the two monolayers was considered identical. From the upper (orange) to the lower (light green) curve, the spontaneous curvature changes from J0 = –0.20 nm–1 to J0 = +0.25 nm–1 with a step of 0.05 nm–1.

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6. Fig. 5. Dependences of the pore energy on the radius in membranes asymmetric in the spontaneous curvature of monolayers (bold black curves): a – Ju = –0.1 nm–1, Jl = –0.3 nm–1; b – Ju = 0, Jl = –0.2 nm–1; c – Ju = +0.1 nm–1, Jl = –0.1 nm–1; d – Ju = +0.2 nm–1, Jl = 0. For comparison, panels a–d also show the dependences of the pore energy on the radius in symmetric membranes, in which the spontaneous curvature of two monolayers is the same and varies from J0 = –0.20 nm–1 (upper orange curves) to J0 = +0.25 nm–1 (lower light green curves) with a step of 0.05 nm–1, similar to Fig. 4.

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