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Identification of electroporation sites in the complex lipid organization of the plasma membrane

The plasma membrane of a biological cell is a complex assembly of lipids and membrane proteins, which tightly regulate transmembrane transport. When a cell is exposed to strong electric field, the membrane integrity becomes transiently disrupted by formation of transmembrane pores. This phenomenon t...

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Autores principales: Rems, Lea, Tang, Xinru, Zhao, Fangwei, Pérez-Conesa, Sergio, Testa, Ilaria, Delemotte, Lucie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912918/
https://www.ncbi.nlm.nih.gov/pubmed/35195069
http://dx.doi.org/10.7554/eLife.74773
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author Rems, Lea
Tang, Xinru
Zhao, Fangwei
Pérez-Conesa, Sergio
Testa, Ilaria
Delemotte, Lucie
author_facet Rems, Lea
Tang, Xinru
Zhao, Fangwei
Pérez-Conesa, Sergio
Testa, Ilaria
Delemotte, Lucie
author_sort Rems, Lea
collection PubMed
description The plasma membrane of a biological cell is a complex assembly of lipids and membrane proteins, which tightly regulate transmembrane transport. When a cell is exposed to strong electric field, the membrane integrity becomes transiently disrupted by formation of transmembrane pores. This phenomenon termed electroporation is already utilized in many rapidly developing applications in medicine including gene therapy, cancer treatment, and treatment of cardiac arrhythmias. However, the molecular mechanisms of electroporation are not yet sufficiently well understood; in particular, it is unclear where exactly pores form in the complex organization of the plasma membrane. In this study, we combine coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis to identify how formation of pores depends on the local lipid organization. We show that pores do not form homogeneously across the membrane, but colocalize with domains that have specific features, the most important being high density of polyunsaturated lipids. We further show that knowing the lipid organization is sufficient to reliably predict poration sites with machine learning. Additionally, by analysing poration kinetics with Bayesian survival analysis we show that poration does not depend solely on local lipid arrangement, but also on membrane mechanical properties and the polarity of the electric field. Finally, we discuss how the combination of atomistic and coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis can guide the design of future experiments and help us to develop an accurate description of plasma membrane electroporation on the whole-cell level. Achieving this will allow us to shift the optimization of electroporation applications from blind trial-and-error approaches to mechanistic-driven design.
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spelling pubmed-89129182022-03-11 Identification of electroporation sites in the complex lipid organization of the plasma membrane Rems, Lea Tang, Xinru Zhao, Fangwei Pérez-Conesa, Sergio Testa, Ilaria Delemotte, Lucie eLife Structural Biology and Molecular Biophysics The plasma membrane of a biological cell is a complex assembly of lipids and membrane proteins, which tightly regulate transmembrane transport. When a cell is exposed to strong electric field, the membrane integrity becomes transiently disrupted by formation of transmembrane pores. This phenomenon termed electroporation is already utilized in many rapidly developing applications in medicine including gene therapy, cancer treatment, and treatment of cardiac arrhythmias. However, the molecular mechanisms of electroporation are not yet sufficiently well understood; in particular, it is unclear where exactly pores form in the complex organization of the plasma membrane. In this study, we combine coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis to identify how formation of pores depends on the local lipid organization. We show that pores do not form homogeneously across the membrane, but colocalize with domains that have specific features, the most important being high density of polyunsaturated lipids. We further show that knowing the lipid organization is sufficient to reliably predict poration sites with machine learning. Additionally, by analysing poration kinetics with Bayesian survival analysis we show that poration does not depend solely on local lipid arrangement, but also on membrane mechanical properties and the polarity of the electric field. Finally, we discuss how the combination of atomistic and coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis can guide the design of future experiments and help us to develop an accurate description of plasma membrane electroporation on the whole-cell level. Achieving this will allow us to shift the optimization of electroporation applications from blind trial-and-error approaches to mechanistic-driven design. eLife Sciences Publications, Ltd 2022-02-23 /pmc/articles/PMC8912918/ /pubmed/35195069 http://dx.doi.org/10.7554/eLife.74773 Text en © 2022, Rems et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Rems, Lea
Tang, Xinru
Zhao, Fangwei
Pérez-Conesa, Sergio
Testa, Ilaria
Delemotte, Lucie
Identification of electroporation sites in the complex lipid organization of the plasma membrane
title Identification of electroporation sites in the complex lipid organization of the plasma membrane
title_full Identification of electroporation sites in the complex lipid organization of the plasma membrane
title_fullStr Identification of electroporation sites in the complex lipid organization of the plasma membrane
title_full_unstemmed Identification of electroporation sites in the complex lipid organization of the plasma membrane
title_short Identification of electroporation sites in the complex lipid organization of the plasma membrane
title_sort identification of electroporation sites in the complex lipid organization of the plasma membrane
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912918/
https://www.ncbi.nlm.nih.gov/pubmed/35195069
http://dx.doi.org/10.7554/eLife.74773
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