(525j) Exploring the Role of Lipid Tail Length on the Structure of Self-Assembled Stratum Corneum Lipids

The barrier function of the human epidermis 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, and free fatty acids of various lengths. While, experimentalists are able to reproduce the lipid organization of intact SC with model systems using synthetic lipids,¹ the role of each lipid in determining 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, we have used molecular dynamics (MD) simulations to study the microscopic behavior of the SC lipids.^2,3 MD simulations of SC systems using atomistic models are typically performed with pre-assembled bilayer structures. However such simulations can suffer from initialization bias due to low lipid mobility and further, simple bilayers are not representative of the complex multilayer structure of the SC.⁴ While self-assembly eliminates any bias associated with assuming a starting structure, the long timescales and large system sizes needed to study multilamellar structures make performing self-assembly using atomistic models infeasible. Thus, we employ computationally efficient coarse-grained (CG) models that have been parameterized using the Multi-State Iterative Boltzmann Inversion (MS-IBI) method² based on simulation data from fully atomistic models.³ Here, we examine mixtures of lesser-studied ceramides, including CERs AP, NP, AS, and NS that form the short periodicity phase (SPP) of the SC lipid matrix. We examine how free fatty acid chain length and CER acyl chain length affects lipid packing and structural properties in multilamellar skin lipid systems in order to compare to experimental work. The simulations show the effect of interdigitation of the lipid tails leading to changes in tail confirmation and lamellar repeat distances, as well as on the stability of the SPP. Through a molecular-level understanding of the packing and formation of these regions, we are able to provide molecular level explanations of the experimental results.⁵

References:

¹J. A. Bouwstra and M. Ponec, “The skin barrier in healthy and diseased state,” Biochimica et Biophysica Acta - Biomembranes. 2006, doi: 10.1016/j.bbamem.2006.06.021.²T. C. Moore, C. R. Iacovella, and C. McCabe, “Development of a Coarse-Grained Water Forcefield via Multistate Iterative Boltzmann Inversion,” Found. Mol. Model. Simulation. Mol. Model. Simul., pp. 37–52, Sep. 2016, doi: 10.1007/978-981-10-1128-3_3.³T. C. Moore, C. R. Iacovella, R. Hartkamp, A. L. Bunge, and C. McCabe, “A Coarse-Grained Model of Stratum Corneum Lipids: Free Fatty Acids and Ceramide NS,” J. Phys. Chem. B, vol. 120, no. 37, pp. 9944–9958, 2016, doi: 10.1021/acs.jpcb.6b08046. ⁴I. Iwai et al., “The human akin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety,” J. Invest. Dermatol., vol. 132, no. 9, pp. 2215–2225, 2012, doi: 10.1038/jid.2012.43. ⁵D. Kessner, A. Ruettinger, M. A. Kiselev, S. Wartewig, and R. H. H. Neubert, “Properties of ceramides and their impact on the stratum corneum structure: A review - Part 2: Stratum corneum lipid model systems,” Skin Pharmacology and Physiology. 2008, doi: 10.1159/000112956.