| 1. |
- Lundborg, Magnus, et al.
(författare)
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Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation
- 2018
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Ingår i: Journal of Structural Biology. - : Academic Press. - 1047-8477 .- 1095-8657. ; 203:2, s. 149-161
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 2. |
- Lundborg, Magnus, et al.
(författare)
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Predicting drug permeability through skin using molecular dynamics simulation
- 2018
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Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 283, s. 269-279
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Tidskriftsartikel (refereegranskat)abstract
- Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin's barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin's barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.
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| 3. |
- Narangifard, Ali, et al.
(författare)
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Molecular Reorganization during the Formation of the Human Skin Barrier Studied In Situ
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 141:5, s. 1243-1253
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Tidskriftsartikel (refereegranskat)abstract
- In vertebrates, skin upholds homeostasis by preventing body water loss. The skin's permeability barrier is located intercellularly in the stratum corneum and consists of stacked lipid lamellae composed of ceramides, cholesterol, and free fatty acids. We have combined cryo-electron microscopy with molecular dynamics modeling and electron microscopy simulation in our analysis of the lamellae's formation, a maturation process beginning in stratum granulosum and ending in stratum corneum. Previously, we have revealed the lipid lamellae's initial- and end-stage molecular organizations. In this study, we reveal two cryo-electron microscopy patterns representing intermediate stages in the lamellae's maturation process: a single-band pattern with 2.0-2.5 nm periodicity and a two-band pattern with 5.5-6.0 nm periodicity, which may be derived from lamellar lipid structures with 4.0-5.0 nm and 5.5-6.0 nm periodicity, respectively. On the basis of the analysis of the data now available on the four maturation stages identified, we can present a tentative molecular model for the complete skin barrier formation process.
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| 4. |
- Narangifard, Ali
(författare)
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Molecular structure of the human skin’s barrier : elucidation, formation and utilization
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main focus of this study is the permeation barrier of human skin. Original cryo-electron microscopic images from near native samples of human epidermis was used as the guiding reference to assemble in silico molecular models and also to assess the possibility of their presence in the barrier. Molecular dynamics and transmission electron microscopy simula- tions have been successively deployed to obtain models closer to a more naturally occurring state and attain simulated electron-microscopic images from them comparable to those from the real cryo-electron microscopy. The important questions that were investigated are: How is the barrier formation initiated? What are the transient structures involved and how do structural transformations advance during the formation process? What final structure does it form into? The results show support for a hydrated and tightly folded cubic structure containing gly- cosylceramides as the starting structure, compatible with reference cryo-electron microscopy images from the topmost layer of the stratum granulosum. Furthermore it is shown how this structure has the ability to collapse into a lamellar structure after deglycosylation and dehydration. Subsequent stages of the development of the barrier are visible in the mi- croscopic data from the lowermost layers of stratum corneum. The data show uniform and non-uniform fine striped patterns. We attempted to arrive at molecular structures that could explain the cryo-electron microscopy patterns. Multiple systems were tested and the ones with the best match were selected as the most plausible model. The same procedure was applied to determine the structure of the fully formed barrier, which is thought to be the ma- jor obstacle for permeation of different substances into the body. It is further demonstrated how an accurate molecular model of the skin’s barrier structure can be utilized to predict some of its physical properties such as its permeability properties or thermotropic behaviour, revealing the capability of computer simulations in situations where the lab experiments are unwieldy or impossible.
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| 5. |
- Wennberg, Christian, et al.
(författare)
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Structural transitions in ceramide cubic phases during formation of the human skin barrier
- 2018
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Ingår i: Biophysical Journal. - : Cell Press. - 0006-3495 .- 1542-0086.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The stratum corneum is the outer-most layer of the human skin, and constitutes the primary barrier to penetration of external substances. The barrier function of the stratum corneum is primarily located to its extracellular space, which consists of long-chain ceramides, free fatty acids and cholesterol organised into a stacked lamellar bilayer structure. Recent experimental studies have shown that these lamellar structures are formed through a structural reorganization of glycosylceramide-based bilayers, folded in three dimensions with a cubic-like symmetry. Here we present coarse-grained molecular dynamics simulations of human ceramide- and glycosylceramide bilayer structures with gyroid cubic symmetry. The bilayer structures with glycosylceramides are able to maintain the cubic symmetry, while the bilayer structures with ceramides collapse into a stacked lamellar bilayer structure as the water content is reduced.
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