Investigating the effects of ceramide variation on lipid organisation in the stratum corneum from molecular dynamics simulations

Shubham Deshpande1, Chloe Frame2, Lingfeng Gui1, Annette Bunge3, Clare McCabe1,2
1School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK
2Dept. of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA
3Dept. of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO, USA

The stratum corneum (SC) is the outermost layer of human skin and serves as the primary barrier against water loss and external damage. The barrier function of skin arises primarily from the highly ordered lipid matrix between skin (corneocyte) cells.1 While the composition of the lipid matrix is known, how individual lipids contribute to lipid organisation and barrier function remains poorly understood. Molecular dynamics (MD) simulations can help address this by providing a molecular-level view of skin lipid organisation, allowing the structural roles of individual lipid components to be investigated in model systems.2

In this work, MD simulations are used to investigate the structural organisation of SC lipids (ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs) using a multiscale modelling approach. Multilayer lipid systems are first self-assembled using coarse-grained (CG)3,4 simulations and subsequently reverse-mapped to atomistic resolution to allow for detailed structural and hydrogen boning analysis. The final atomistic systems consist of six leaflets (three bilayers) and provide a practical representation of the short periodicity phase of the SC. Both pure CER systems and mixtures containing CERs with CHOL and free fatty acids in a 1:0.5:1 molar ratio are examined and metrics such as area per lipid (APL), bilayer height, hydrogen order parameters (SCH), and hydrogen bonding networks determined.5 The results demonstrate how slight differences in CER headgroup and tail structure can influence lipid packing and organisation, along with highlighting the capability of the multiscale approach used to complement and explain experimental observations.

References:
1. Bouwstra, J.A. et (2023) ‘The skin barrier: an extraordinary interface with an exceptional lipid organization’, Progress in lipid research, 92,101252.

2. Shamaprasad, P. et al. (2022) ‘Using molecular simulation to understand the skin barrier’, Progress in lipid research, 88, 101184.

3. Moore, T.C. et al. (2018) ‘Molecular dynamics simulations of stratum corneum lipid mixtures: a multiscale perspective,’ Biochemical and Biophysical Res. Com., 498(2), 313.

4. Frame, C.O. et al. (2025) ‘New coarse-grained models for stratum corneum ceramides reveal headgroup-dependent structural organization’, J. Physical Chemistry B, 129(47), 12167.

5. Frame, C.O. et al. (2026) ‘Multiscale simulation of stratum corneum lipid mixtures: effects of ceramide headgroups on structural organization and hydrogen bonding networks’, Int. J. of Pharmaceutics, 691, 126573.