(545h) Multiscale Modeling of Stratum Corneum Lipids to Understand the Barrier Function of Skin

The barrier function of the human skin is primarily located in the stratum corneum (SC), which is composed of corneocytes surrounded by a dense, lamellar lipid matrix made up of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs) of various lengths. While experimentalists can reproduce the lipid organization of intact SC with model systems using synthetic lipids,¹ the role of each lipid in the formation of the molecular structure of the SC, and hence the barrier properties of skin, is not well understood due to the complex nature of the SC lipid matrix. To address this need, atomistic molecular dynamics (MD) simulations of pre-assembled lipids in primarily bilayer configurations have been used to study the behavior of the SC lipids.² However, such simulations can suffer from configurational bias due to low lipid mobility, and further, simple bilayers cannot sufficiently represent the complexity of SC multilayer structures. Thus, in order to emulate the experimental model membrane formation at long timescales and large system sizes, we developed computationally efficient coarse-grained (CG) models using the Multi-State Iterative Boltzmann Inversion (MS-IBI) method.³ Here, we begin our multiscale strategy of understanding SC lamella with the CG self-assembly of large complex multilayer mixtures of multiple CERs, CHOL, and FFAs that match previously examined experimental compositions. Specifically, we go beyond the commonly studied CER NS to simulate mixtures with CERs NS, NP, AS, and AP as well as understanding the role of FFA tail length distribution. Atomistic configurations generated by back-mapping the self-assembled multi-lamellar CG configurations provide insights into lipid organization and structure of experimental model membranes. This multiscale approach accumulates simulation and collaborative experiments providing a holistic picture of structural properties, hydrogen bonding capabilities, and neutron scattering studies to better understand the relationship between composition of SC lipids and the barrier function of skin.

References

(1) Bouwstra, J. A.; Ponec, M. The Skin Barrier in Healthy and Diseased State. Biochimica et Biophysica Acta - Biomembranes. 2006. https://doi.org/10.1016/j.bbamem.2006.06.021.

(2) Shamaprasad, P.; Frame, C. O.; Moore, T. C.; Yang, A.; Iacovella, C. R.; Bouwstra, J. A.; Bunge, A. L.; McCabe, C. Using Molecular Simulation to Understand the Skin Barrier. Prog. Lipid Res. 2022, 88. https://doi.org/10.1016/j.plipres.2022.101184.

(3) Moore, T. C.; Iacovella, C. R.; McCabe, C. Derivation of Coarse-Grained Potentials via Multistate Iterative Boltzmann Inversion. J. Chem. Phys. 2014. https://doi.org/10.1063/1.4880555.