Simulation Study of the Structure and Phase Behavior of Ceramide Bilayers and the Role of Lipid Headgroup Chemistry

Abstract

Ceramides are known to be a key component of the stratum corneum, the outermost protective layer of the skin that controls barrier function. In this work, molecular dynamics simulations are used to examine the behavior of ceramide bilayers, focusing on non-hydroxy sphingosine (NS) and non-hydroxy phytosphingosine (NP) ceramides. Here, we propose a modified version of the CHARMM force field for ceramide simulation, which is directly compared to the more commonly used GROMOS-based force field of Berger (Biophys. J. 1997, 72); while both force fields are shown to closely match experiment from a structural standpoint at the physiological temperature of skin, the modified CHARMM force field is better able to capture the thermotropic phase transitions observed in experiment. The role of ceramide chemistry and its impact on structural ordering is examined by comparing ceramide NS to NP, using the validated CHARMM-based force field. These simulations demonstrate that changing from ceramide NS to NP results in changes to the orientation of the OH groups in the lipid headgroups. The arrangement of OH groups perpendicular to the bilayer normal for ceramide NP, verse parallel for NS, results in the formation of a distinct hydrogen bonding network, that is ultimately responsible for shifting the gel-to-liquid phase transition to higher temperature, in direct agreement with experiment.

Coarse-Grain Simulations of Skin Ceramide NS with Newly Derived Parameters Clarify Structure of Melted Phase

“…Another problem of the coarse grain representation is its inability to reproduce tilt of ceramide tails. 70,71 Whereas lipids are tilted by around 22° with respect to the z-axis in the atomistic simulation, in good agreement with a value of 24.3° reported by Guo et al, 30 they exhibit negligible tilt in the CG simulations. It also seems that coarse grain force field overestimates area compressibility modulus in the gel state (see Table 2), albeit is has been shown to perform well for liquid crystal state.…”

Comparative atomic-scale hydration of the ceramide and phosphocholine headgroup in solution and bilayer environments

“…35 In addition the ceramide model used here was tested to ensure that the chain melting temperature and the area per lipid in the gel phase are in agreement with experimental measurements. 36 However, it is not clear whether this agreement would extend to a mixed lipid system. Ceramide has a propensity to condense bilayers and at high ceramide concentrations a gel phase would be observed at physiological temperatures.…”

“…The simulations were carried out using the molecular dynamics (MD) simulation program LAMMPS. 34 CHARMM (C36) potentials 35 were used for the DOPC and a recent model, 36 based on CHARMM was used for the ceramide whilst water was modelled using the TIP3P parameters. 37,38 The analysis presented here focuses on the simulation of the bilayer containing 180 DOPC molecules and 20 ceramide molecules, whilst the remaining bilayers are used for analysis of the bulk properties.…”

Novel Fused 1h- Imidazo[1,2-B] Pyrazole Analogues as Anti-Inflammatory and Analgesic Agents With Their Molecular Docking Studies Against Cox-1 and Cox-2

“…Analgesic activity was assessed by tail-flick method [29], Swiss albino mice of either sex weighing 20-25 g in group of five were selected by random sampling technique. The newly synthesised compounds and the anlagen as reference standard drug was orally administered at a dose level of 10 mg kg -1 body weight of the mice.…”