Effect of Ceramide Tail Length on the Structure of Model Stratum Corneum Lipid Bilayers

Abstract

Lipid bilayers composed of non-hydroxy sphingosine ceramide (CER NS), cholesterol (CHOL), and free fatty acids (FFAs), which are components of the human skin barrier, are studied via molecular dynamics simulations. Since mixtures of these lipids exist in dense gel phases with little molecular mobility at physiological conditions, care must be taken to ensure that the simulations become decorrelated from the initial conditions. Thus, we propose and validate an equilibration protocol based on simulated tempering, in which the simulation takes a random walk through temperature space, allowing the system to break out of metastable configurations and hence become decorrelated from its initial configuration. After validating the equilibration protocol, which we refer to as random-walk molecular dynamics, the effects of the lipid composition and ceramide tail length on bilayer properties are studied. Systems containing pure CER NS, CER NS + CHOL, and CER NS + CHOL + FFA, with the CER NS fatty acid tail length varied within each CER NS-CHOL-FFA composition, are simulated. The bilayer thickness is found to depend on the structure of the center of the bilayer, which arises as a result of the tail-length asymmetry between the lipids studied. The hydrogen bonding between the lipid headgroups and with water is found to change with the overall lipid composition, but is mostly independent of the CER fatty acid tail length. Subtle differences in the lateral packing of the lipid tails are also found as a function of CER tail length. Overall, these results provide insight into the experimentally observed trend of altered barrier properties in skin systems where there are more CERs with shorter tails present.

Molecular Reorganization during the Formation of the Human Skin Barrier Studied In Situ

“…In the simulated skin lipid model system, the transformation is not complete, and stabilizes at about 35-40% ceramides in the splayed conformation and with remaining ceramides in the hairpin conformation. However, it shows that the ceramides have a tendency to spontaneously extend from the hairpin-to the splayed chain conformation, which also is supported by earlier data (Sovová et al, 2015;Moore et al, 2016;Wennberg et al, 2018;Wang and Klauda, 2019). The driving force for the preferred splayed conformation over the hairpin conformation may be that the stabilizing Hbonding system between the two hydrocarbon matrices is better preserved in the splayed conformation when shielded from the competition of water.…”

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis

“…In our primary human airway epithelial model, we found increased production of several proinflammatory mediators in cultures derived from adults with advanced CF lung disease. The effects of altered membrane microdomain abundance on relative fluidity and stability of transmembrane receptors involved in inflammatory responses and activity of ion channels remains poorly understood (15,45,46). Notably, Abu-Arish and colleagues recently demonstrated that epithelial cells respond to secretagogues by forming clusters of CFTR in ceramide-rich membrane microdomains via an acid sphingomyelinase-dependent mechanism to increase transepithelial secretion (47).…”

Stratum corneum lipid matrix with unusual packing: A molecular dynamics study

“…There are, however, some works that study the LM lipids properties and assembling, or the potential of some chemicals to cross the skin barrier. These studies present several different LM models, varying in terms of composition, packing, and complexity [22][23][24][25]. However, like in any computational simulation, the ability to correlate the simulation results with the real world depends on the strength and reliability of the computational models.…”