Insights Into the Barrier Function Of The Stratum Corneum Lipid Matrix Using A Multiscale Molecular Simulation Approach

Abstract

The stratum corneum (SC), the outermost layer of the skin, serves as a crucial barrier, protecting against environmental stressors and preventing excessive water loss. It consists of corneocytes—dead skin cells—embedded in a dense lipid matrix. This matrix, primarily composed of cholesterol, free fatty acids, and ceramides (CERs), is essential for the skin's barrier function. CERs, with their diverse headgroup chemistries and chain lengths, are particularly important for maintaining the SC's structural organization and, consequently, its barrier properties. Disruptions in lipid composition, as seen in skin conditions like atopic dermatitis (eczema) and psoriasis, can compromise this barrier. Such disruptions often lead to altered lateral (2-D) and lamellar (layered) lipid organization, reduced lipid packing, and increased permeability. Understanding the molecular mechanisms behind these changes is critical for developing effective skincare treatments and strategies to repair compromised skin barriers. This work addresses key gaps in the SC lipid research by leveraging molecular dynamics (MD) simulations to explore the role of CERs in the structural and functional organization of SC lipids. MD simulations complement experimental methods by providing molecular-level detail, allowing researchers to study nanoscale interactions and dynamic processes that are often difficult to capture experimentally. To tackle the complexity of lipid organization in the SC, a multiscale simulation approach was used, combining all-atom and coarse-grained (CG) models. By integrating these two modeling approaches, the research focuses on the contribution of CERs to the lateral and lamellar organization of lipids in the SC. A key emphasis was placed on understanding the short periodicity phase—a specific lipid arrangement critical to the SC’s barrier function—and its relationship to overall barrier properties. This work delves into how the chemical structure of CER headgroups, the dynamics of lipid tails, and variations in lipid composition influence key properties such as lipid packing, hydrogen bonding networks, and permeability. Notable outcomes include the development of new CG models for CERs and simulations of complex lipid mixtures that mimic the structural differences between healthy and diseased SC. These models provide valuable insights into the molecular basis of SC lipid organization and dysfunction, offering a foundation for developing strategies to repair and improve compromised skin barriers. This research bridges the gap between detailed molecular understanding and practical applications in skincare and barrier repair.