(291b) Simulation Study of the Impact of Cholesterol on Ceramide-Based Lipid Bilayers

The ability of the skin to regulate bodily functions and act as an effective barrier to chemical penetrants is controlled by the thin, outermost layer, known as the stratum corneum. This layer is predominantly composed of dead skin cells—corneocytes—embedded in a rich lipid matrix composed of ceramides, cholesterol, and free fatty acids. The lipids control the barrier function of the skin, however, the molecular level organization of the species and their role in maintaining the barrier function of the skin is not well understood. Here, the properties of ceramide bilayers are examined using models derived from the CHARMM36 forcefield [1] with missing parameters and charges determined from density functional theory calculations [2].  The crystallographic, structural and thermotropic behavior of pure ceramide systems are found to agree closely with experiment, validating the model [2].   To understand the role of cholesterol, mixtures of ceramides and cholesterol in a bilayer configuration are examined and compared to pure ceramide bilayers. Due to diffusion limitations, an adaptation of the replica exchange molecular dynamics algorithm is used to compute robust, low energy configurations of mixed bilayers.  The equilibrium spatial arrangements of cholesterol are examined to determine the predominant morphological motifs as a function of cholesterol concentration.  Furthermore, examination of the hydrogen bonding network in the bilayer reveals a reduction in ceramide-ceramide hydrogen bonding due to the presence of cholesterol.

[1] Klauda, J. B.; Venable, R. M.; et al., Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types. J.  Phys. Chem. B 2010, 114 (23), 7830-7843.

[2] Guo, S. Moore, T. C., Iacovella, C. R., Strickland, L. A., McCabe, C., Simulations Study of the Structure and Phase Behavior of Ceramide Bilayers and the Role of Lipid Headgroup Chemistry, J. Chem. Theory Comput. 2013, 9 (11), 5116-5126.