Multiscale simulation of stratum corneum lipid mixtures: effects of ceramide headgroups on structural organization and hydrogen bonding networks

The barrier function of the outermost layer of human skin, the stratum corneum (SC), arises from its multilamellar lipid matrix composed primarily of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs). Coarse-grained (CG) and atomistic molecular dynamics simulations have been used to study self-assembled multilayers comprising CERs NS, NP, AS, and AP, in pure CER systems and mixtures of CERs with CHOL and FFAs. Equilibrated CG configurations were reverse-mapped to recover atomistic details and analyzed to extract structures and hydrogen bonding. Simulations of pure CERs agreed with experimental trends: phytosphingosine CERs (NP and AP) exhibited more Cdouble bondO hydrogen bonds, consistent with lower amide I FTIR frequencies, than their sphingosine counterparts (NS and AS). Likewise, non-hydroxy CERs (NS and NP) exhibited more Cdouble bondO hydrogen bonding than their α-hydroxy analogs (AS and AP). CER mixtures with CHOL and FFA showed reduced Cdouble bondO hydrogen bonding compared to pure CERs, though this effect depended on water content. Hydroxyl location was critical: OH on the phytosphingosine base increased Cdouble bondO hydrogen bonding, whereas the α-hydroxy on the acyl chain reduced it. In CER NP:AP mixtures with CHOL and FFA, simulations reproduced the experimental repeat distances of the NP-rich and AP-rich systems despite differences in hydrogen bonding. Simulations of multicomponent mixtures resembling the SC model of Bouwstra demonstrated the dominant effect of chain-length distribution, rather than CER hydrogen bonding, on permeability. This work shows how multiscale modeling integrated with experiments can uncover molecular mechanisms linking composition and SC barrier structure to interpret experimental results.