| dc.description.abstract | The skin serves as the body’s primary barrier against external chemicals and pathogens as well as water loss. This protective function is localized to the skin’s outermost layer, the stratum corneum. The stratum corneum consists of corneocyte cells embedded within an extracellular lipid matrix, comprising ceramides, cholesterol, and free fatty acids. Skin conditions like eczema and psoriasis, that disrupt its barrier function, alter the lipid composition and arrangement within the stratum corneum. Understanding this connection between lipid composition, arrangement and barrier function requires insight into the unique structure of the lipid matrix. Several hypothetical lipid configurations within the stratum corneum have been proposed based upon experimental methods. However, these techniques often lack the molecular-level precision required to achieve a consensus on lipid organization. Molecular dynamics simulations offer a promising solution to bridge this gap, providing a three-dimensional, molecular-level representation of membrane structures.
This dissertation employs molecular dynamics simulations to investigate lipid organization within the short and long periodicity phases, which are the predominant lamellar phases of the stratum corneum lipid matrix. A multiscale approach is utilized, that combines efficient coarse-grained models, capable of exploring extended time scales, with precise atomistic models. First, a combined simulation and experimental approach is employed to explore the phase behavior, in-plane morphology, and the impact of molecular conformation and cholesterol composition on the short periodicity phase. The results of this study emphasize the importance of examining multilayer structures for accurate comparisons with experimental membranes. The feasibility of various lipid arrangements of the short and long periodicity phases is further assessed by comparing atomistic simulations of these structures to experimental data. Finally, the coarse-grained model is extended to simulate self-assembly into the long periodicity phase, which is considered a critical component contributing to the skin's permeability barrier. These findings provide a foundation for future investigations into structural variations in healthy and diseased states, the effects of topical formulations, and permeability of the stratum corneum lipid matrix. | |
