(704h) Self-Assembly Simulations of Stratum Corneum Lipid Mixtures

The barrier function of human skin is localized to its outermost layer, the stratum corneum (SC); specifically, the lipid matrix which surrounds dead, flat corneocytes is thought to be the main barrier to chemical penetration through the skin. The chemical makeup of the SC lipids is known, but the molecular level details of its structure are not, in part due to the fact that 14 unique lipids have been identified in the SC. As such, experiments often consider simplified mixtures of synthetic lipids whose composition can be precisely controlled, however, even simple systems lead to different hypotheses (e.g., whether two-tailed ceramide lipids adopt a hairpin or extended conformation in lamellar structures). Molecular simulation is an important complement to these experimental studies, as simulation provides a direct 3-D molecular-level resolution and precise control over composition. Thus far, most simulation studies of SC lipids have focused on pre-assembled structures. While such studies have offered much insight into lipid-lipid and lipid-water interactions, it is possible that the preassembled structures are not representative of the molecular structures in the skin, given the low diffusion coefficient of the lipids and the fact that single bilayers are considered, rather than experimentally/biologically relevant multilayer structures. As such, self-assembled structures would provide a more realistic structure of SC lipid systems, but the timescales required to access self-assembly, and the system sizes needed to model multilayer structures, are likely prohibitive for atomistically detailed models, necessitating the use of coarse-grained (CG) models.

In this work, we present the results of the derivation and validation of CG models of the lipids present in the SC: ceramides, cholesterol and free fatty acids. The potentials were derived via multi-state and multi-ensemble iterative Boltzmann inversion [1], based on simulations of fully atomistic models [2]. Validation is first performed on preassembled bilayers and multilayers, where results are compared to corresponding atomistic simulations. Self-assembly into lamellar structures was observed, and the details of the process are elucidated. We find that the intramolecular conformations of the ceramides are dependent on the lipid composition of the system, with a greater number of different components giving rise to a greater fraction of extended or linear ceramide conformations, compared to less diverse systems which show a greater fraction of hairpin ceramide conformations. Thus, these self-assembled structures provide clear insight into the experimentally proposed

References

[1]. Moore, T. C., Iacovella, C. R. & McCabe, C. Derivation of coarse-grained potentials via multistate iterative Boltzmann inversion. J. Chem. Phys. 140, 224104 (2014).

[2]. Moore, T. C., Iacovella, C. R., Hartkamp, R., Bunge, A. L. & McCabe, C. A Coarse-Grained Model of Stratum Corneum Lipids: Free Fatty Acids and Ceramide NS. J. Phys. Chem. B 120, 9944–9958 (2016).