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Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation
ERCO Pharma AB, Sci Life Lab, Solna, Sweden..
ERCO Pharma AB, Sci Life Lab, Solna, Sweden.;Karolinska Inst, Dept Med, Solna MedS, Solna, Sweden..
KTH, School of Engineering Sciences (SCI), Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre. ERCO Pharma AB, Sci Life Lab, Solna, Sweden..ORCID iD: 0000-0002-4591-9809
KTH, School of Engineering Sciences (SCI), Physics. KTH, Centres, SeRC - Swedish e-Science Research Centre. Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.ORCID iD: 0000-0002-2734-2794
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2018 (English)In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 203, no 2, p. 149-161Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Academic Press, 2018. Vol. 203, no 2, p. 149-161
Keywords [en]
Stratum corneum, Skin permeation, Cryo-EM, Molecular dynamics simulation, Lipids
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-232599DOI: 10.1016/j.jsb.2018.04.005ISI: 000437807900010PubMedID: 29702212Scopus ID: 2-s2.0-85046730207OAI: oai:DiVA.org:kth-232599DiVA, id: diva2:1236142
Funder
Swedish Research CouncilWenner-Gren FoundationsSwedish Society of MedicineSwedish e‐Science Research Center
Note

QC 20180731

Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-07-31Bibliographically approved

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Wennberg, Christian L.Lindahl, Erik

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