(741a) Multiscale Modeling of Stratum Corneum Lipid Mixtures

The barrier function of human skin is known to be localized to its outermost layer, the stratum corneum (SC), which is composed of a dense lipid matrix surrounding dead skin cells (corneocytes). Since the lipid matrix presents the only continuous path through the SC, determining the link between composition and structure is essential for understanding barrier function. While the chemical makeup of the SC lipids is known, the molecular level details of the structure is not, in part due to the fact that over 14 unique ceramides of varying chain length, along with cholesterol, and free fatty acids, have thus far been identified. As such, experiments often consider simplified mixtures of synthetic lipids, whose composition can be precisely controlled, in order to gain insight into this complex system. However, even simple systems can lead to different hypotheses (e.g., whether two-tailed ceramide lipids adopt a hairpin or extended conformation in lamellar structures) due to the inability to precisely locate different lipid species and their confirmations. Molecular simulation is an important complement to these experimental studies, as simulation provides a direct 3D molecular-level resolution and precise control over composition.

We present both atomistic and coarse-grained (CG) molecular dynamics simulations of simplified mixtures of SC lipids, namely cholesterol, free fatty acid, and ceramides. Atomistic simulations of pre-assembled bilayer structures are used to probe the impact of the individual lipid components on structure and examine the role of ceramide tail length [1]. CG MD simulations are used to examine self-assembled structures that complement the atomistic studies. The CG force fields were parameterized using the multi-state and multi-ensemble iterative Boltzmann inversion method [1] based on simulation data from fully atomistic models [3]. The CG results examine structural differences between bilayer and multilayer structures, and due to their computational efficiency, allow a larger range of parameters to be explored, including the role of free fatty acid chain length. The CG results also demonstrate that the intramolecular conformations of the ceramides are dependent on the lipid composition of the system, where increasing the number of lipid components gives rise to a greater fraction of extended ceramide conformations, helping to elucidate the 3D structure of these mixtures.

References

[1] Moore T.C., Hartkamp R., Iacovella C.R., Bunge A.L., McCabe C. The Influence of Ceramide Tail Length on the Structure of Bilayers Composed of Stratum Corneum Lipids, Biophysical Journal, 2018 114, 113-125
[2] Moore, T. C., Iacovella, C. R. & McCabe, C. Derivation of coarse-grained potentials via multistate iterative Boltzmann inversion. J. Chem. Phys. 2014, 140, 224104
[3] 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,” Journal of Physical Chemistry B, 120(37) 9944-9958 (2016).