Investigating and developing skin lipid models for molecular dynamics.

Abstract

The stratum corneum (SC) is the outermost layer of the skin, and is responsible for the skin’s barrier properties. The main diffusive pathway across the intact SC is through an extra-cellular lipid mixture, termed the lipid matrix. It is therefore imperative that a detailed understanding of the skin barrier is obtained to inform processes such as the removal of chemical agents from the skin, or improved transdermal delivery of pharmaceuticals. Despite its importance, much remains unknown about the structure of the lipid matrix. While molecular dynamics poses a powerful tool for skin lipid investigation, such simulations are difficult to validate, owing to the lack of experimental data. To address these validation concerns, independent comparative forcefield analyses of skin lipid models, specifically cholesterol and sphingomyelin /ceramides, is presented. Where current forcefields show sub-optimal behaviour, new models are (re-)parameterised. The resulting validated C36-FBparameter set is subsequently used to study the tri-layer model, a proposed molecular arrangement of the SC lipid matrix, revealing the model poorly resembles electron micrographs data. As highlighted in this work, skin lipids exhibit slow dynamics, and thus the initial simulation configuration, which is likely inaccurate, will bias the remaining simulation. A skin lipid coarse-grained forcefield would go someway in addressing this issue. As such, a coarse-grain water model is developed, the BMW-FB model, and represents the initial step in the development of such a forcefield.

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Identifiers

ORCID for Jack Sawdon: orcid.org/0009-0009-4074-6361

ORCID for Jonathan Essex: orcid.org/0000-0003-2639-2746

ORCID for Syma Khalid: orcid.org/0000-0002-3694-5044

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