Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation
Open accessAbstract
In the present study we have analyzed the molecular structure and function of the human skin's permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin. The skin's barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin - the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure's detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial. Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models' lipid composition was to that reported in human stratum corneum, the better was the match between the models' simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model's calculated water permeability and thermotropic behaviour were found compatible with that of human skin. The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems.
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The characteristic EO structure is important for the formation and stabilization of lipid organization in the lipid lamellae.
“EO ceramides are epidermisspecific ceramide classes, and their characteristic EO structure is important for the formation and stabilization of lipid organization in the lipid lamellae (18,19).”
From Comparative profiling and comprehensive quantification of stratum corneum ceramides in humans and mice by LC/MS/MS (2020) · cites this paper as [19]
In Results §3.1 (page not available), changing CER EOS content alters the modeled lipid lamellae’s periodicity, and a model containing 5% CER EOS best matches the cryo-EM images. Discussion §4.1 likewise says adding CER EOS helps reproduce the observed periodicity. These findings support a role in lamellar organization, but the paper does not establish that the characteristic EO structure is important for its formation or stabilization. (LLM, conf=0.83)
Experimental — accuracy not yet measuredEO ceramides are epidermis-specific ceramide classes.
“EO ceramides are epidermisspecific ceramide classes, and their characteristic EO structure is important for the formation and stabilization of lipid organization in the lipid lamellae (18,19).”
From Comparative profiling and comprehensive quantification of stratum corneum ceramides in humans and mice by LC/MS/MS (2020) · cites this paper as [19]
Section 4.2 (page unavailable) identifies CER EOS as a component of the human stratum corneum lipid structure, and section 4.1 reports that adding it brings the model’s lamellar periodicity closer to the observed value. The copy does not establish that EO ceramide classes are specific to the epidermis, nor does it directly show that their EO structure stabilizes the lamellae. (LLM, conf=0.83)
Experimental — accuracy not yet measured
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- Authors
- Lundborg, M., Narangifard, A., Wennberg, C. L., Lindahl, E., Daneholt, B., & Norlén, L.
- Affiliations
- Science for Life Laboratory (SE)
- Stockholm University (SE)
- Karolinska Institutet (SE)
- Venue
- Journal of Structural Biology
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 203
- Issue
- 2
- Pages
- 149-161
- ISSN
- 1047-8477 (ISSN-L)
- OpenAlex
- W2799749633
- Cited by
- 77
- References
- 74
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 7 · 2023: 7 · 2022: 11 · 2021: 10 · 2020: 13 · 2019: 10 · 2018: 5
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Structural Biology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Swedish National Infrastructure for Computing
- Welander foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- skin permeability barrier, stratum corneum, intercellular lipids, cholesterol, free fatty acids, lipid composition, water permeability, molecular dynamics model
- MeSH terms
- Animals, Ceramides, Humans, Lipid Bilayers, Skin, Cryoelectron Microscopy, Molecular Dynamics Simulation
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