Models for the Stratum Corneum Lipid Matrix: Effects of Ceramide Concentration, Ceramide Hydroxylation, and Free Fatty Acid Protonation

The primary barrier of the skin is provided by the outer layer known as the stratum corneum, making it the active target for transdermal drug delivery. A repeating structure of the SC known as the short periodicity phase is modeled as a bilayer composed of ceramides (Cer), cholesterol (Chol), and free fatty acids (FFA). This study simulates Cer/Chol/FFA bilayers composed of N-lignoceroylsphingosine, alpha-lignoceroyl-phytosphingosine, Chol, deprotonated lignoceric acid, and protonated lignoceric acid using the CHARMM36 force field to study the effects of Cer concentration, Cer hydroxylation, and FFA protonation. Calculated bilayer properties include surface area per lipid, area compressibility, deuterium order parameters, average Chol tilt angle, neutron scattering length density (NSLD) profiles, electron density profiles, bilayer thicknesses, interdigitation, hydrogen bonding, lipid clustering, and two-dimensional radial distribution functions. On the basis of comparison of NSLD profiles, the effect of Cer hydroxylation is eliminated as a factor causing bilayer thinning relative to experiment, suggesting other reasons for this experimental-simulation mismatch. Cer concentration, Cer hydroxylation, and FFA protonation all cause significant changes, but the degree of change depends on the specific property. Increasing Cer concentration induces transitions in Cer lipids from postured to hunched conformations, although both conformations possess high chain order. FFA protonation tends to strongly influence properties of the FFA while not perturbing other lipids or the overall bilayer as significantly.