Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation

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.

Predicting Skin Permeability by Means of Computational Approaches: Reliability and Caveats in Pharmaceutical Studies

“…The barrier properties of human skin have been analyzed in silico, simulating electron microscopy patterns on molecular dynamics simulations of a bilayer model. These results have been validated against cryo-electron microscopy data from near native skin 195,196 , showing a thermodynamically stable model and results compatible with values from human skin. Rocco et al 197 applied Steered Molecular Dynamics (SMD) of 80 compounds from Flynn's refined database 198 on a SC model, to obtain lipophilicity and diffusion parameters.…”

Stratum corneum lipid matrix with unusual packing: A molecular dynamics study

“…It was interesting to note that the decrease of PMF when the NRD inserts on the lipid interior was similar for the three lipid systems, namely around 10∼12Kcal/mol. Magnus Lundborg and collaborators published recently two extensive works in which they also developed an LM model based on Iwai work, although the final lipid composition and configuration were changed [56,57]. Their model also presented stability with the splayed CER and some tilt in the zone where the FFA are located, remarks that are also presented in one recent work of neutron diffraction of skin lipids [58].…”

Comparative profiling and comprehensive quantification of stratum corneum ceramides in humans and mice by LC/MS/MS

“…Alteration of ceramide class composition and reductions in the total amount of ceramides have been observed in the SC of atopic dermatitis patients (15)(16)(17). 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). A portion of EO-ceramides are converted into protein-bound ceramides (P-O-ceramides) ( Fig.…”