The stratum corneum (SC), the outermost layer of the skin, is vital for preventing water loss and shielding the body from external threats. This barrier function depends heavily on its unique structure—keratin-filled cells (corneocytes) embedded in a lipid matrix made up of ceramides, cholesterol, and free fatty acids. Ceramides, the dominant lipid class in this matrix, directly influence barrier quality. Notably, different ceramide species have different effects: ceramide NS is linked to impaired barriers, while ceramide NP is associated with healthy, intact skin. Alterations in the NS-to-NP ratio are observed in skin conditions like atopic dermatitis. Previous simulation studies struggled to isolate the molecular basis for these differences due to inconsistent methodologies. This study systematically compares ceramide NS and NP-containing lipid bilayers using unified simulation conditions to uncover the structural basis of their differing permeability properties.
Methods
Molecular dynamics simulations were conducted using bilayers composed of an equimolar ratio of ceramide (either NS or NP), cholesterol, and lignoceric acid. The CHARMM36 force field, modified to accurately model ceramide NP, was used throughout. Water permeability, a key metric of barrier integrity, was assessed using a constrained water permeation method. Structural, conformational, and hydrogen bonding properties were also analyzed to understand differences in lipid behavior and packing.
Key Findings
• Ceramide NP-containing membranes exhibited significantly lower water permeability—about half that of ceramide NS-containing membranes—highlighting its superior barrier function.
• Differences in permeability were mainly attributed to variations in the Potential of Mean Constraint Force (PMcF) profiles, while diffusion coefficients remained similar.
• Subtle shifts in lipid density were observed; NP systems showed more interdigitation of lipids and central localization of cholesterol and lignoceric acid, indicating tighter packing.
• Ceramide NP favored a “posturing” conformation, with wider chain spacing and hydroxyl groups oriented outward, enhancing interactions with water. Ceramide NS adopted a “hunched” conformation, with inward-facing hydroxyls.
• NP-based bilayers exhibited more lipid-water hydrogen bonding and less lipid-lipid bonding, aligning with their lower permeability and tighter packing.
This study confirms that the ceramide species in the SC lipid matrix directly influences water permeability and structural integrity. By using consistent methods and force fields, it provides compelling evidence that ceramide NP forms a more effective barrier than ceramide NS. The molecular mechanisms ranging from conformation and lipid packing to hydrogen bonding clarify how ceramide composition affects the skin’s defense against dehydration and external irritants. These insights reinforce the importance of ceramide NP in skin barrier restoration strategies and suggest that future work should explore mixed ceramide systems and less hydrated models to better reflect in vivo conditions.
Link to the study: https://pubs.acs.org/doi/full/10.1021/acs.molpharmaceut.5c00580
