Presence of Different Ceramide Species Modulates Barrier Function and Structure of Stratum Corneum Lipid Membranes: Insights from Molecular Dynamics Simulations

Ceramides, as major components of the human stratum corneum's (SC) lipid matrix, are considered crucial for regulating the skin's barrier function against the ingress of exogenous substances as well as to prevent water loss through the skin. Multiple clinical and experimental studies found different classes of ceramide species to affect the skin barrier nonuniformly, with some ceramides being associated with an impaired skin barrier, such as ceramide NS, while others are associated with a healthy, unimpaired skin, e.g., ceramide NP. This study investigates how the presence of these two ceramide classes in an SC lipid bilayer membrane influences the water permeability as well as the structure of the bilayer using molecular dynamics (MD) simulations. To this end, simulated membranes comprising free fatty acids, cholesterol, as well as either ceramide NS or ceramide NP were systematically compared in regard to differences in the membrane structure and water permeability, as well as to results found in the literature. The simulation found ceramide NP-containing membranes to have a significantly lower water permeability than ceramide NS-containing systems, with the permeability values of NP-based systems being almost half of those of the NS-based systems. Furthermore, the simulation also showed significant structural differences between the two systems in terms of headgroup conformation and lipid positioning in the membrane, hinting toward the molecular mechanisms underpinning the differences in permeability of the two systems. In conclusion, the MD simulation was able to reproduce effects of the presence of different ceramide species in the membrane that are consistent with experimental as well as clinical studies on skin barrier function and drug delivery and validate previous simulation-based investigations into SC lipid bilayer permeability.