New Coarse-Grained Models for Stratum Corneum Ceramides Reveal Headgroup-Dependent Structural Organization.

The stratum corneum (SC), the outermost layer of human skin, owes its barrier function to highly ordered lipid lamellae composed primarily of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs). Molecular dynamics simulations offer the opportunity to gain valuable insights into the structural organization of lipids, complementing experimental approaches. However, simulations using atomistic models are computationally expensive when studying the large, multilamellar structures characteristic of the SC. Coarse-grained (CG) models of SC lipids provide an efficient alternative but have largely been limited to CER NS. In this work, a previously developed Multistate Iterative Boltzmann Inversion (MS-IBI) CG model for CER NS has been extended to three additional CER subclasses─CERs NP, AP, and AS─which differ from CER NS in headgroup hydroxylation. By leveraging structural similarity and transferring nonbonded interaction parameters for CER NS hydroxyl groups, we have developed new models with minimal reparameterization. The models have been validated against atomistic simulations of both pure and mixed bilayers containing CHOL and FFA. To capture the multilamellar organization, six-leaflet multilayers were self-assembled. The resulting CG systems exhibited lamellar organization, chain order, and repeat distances consistent with the available experimental data. Comparisons across CER subclasses revealed that headgroup hydroxylation influences lipid packing, chain tilt, and whether the CER tails exhibit a hairpin or extended conformation. This work demonstrates the flexibility and transferability of the MS-IBI approach and provides CG models for key CER subclasses in human SC, enabling large-scale simulations of realistic SC lipid compositions beyond the reach of atomistic models.