Structural Changes in Ceramide Bilayers Rationalize Increased Permeation through Stratum Corneum Models with Shorter Acyl Tails

Ceramides are indispensable constituents
of the stratum corneum
(SC), the uppermost impermeable layer of human skin. Ceramides with
shorter (four- to eight-carbon acyl chains) fatty acid chains increase
skin and model membrane permeability, while further shortening of
the chain leads to increased resistance to penetration almost as good
as that of ceramides from healthy skin (24 carbons long on average).
Here we address the extent to which the atomistic CHARMM36 and coarse-grain
MARTINI molecular dynamics (MD) simulations reflect the skin permeability
data. As a result, we observed the same bell-shaped permeability trend
for water that was observed in the skin and multilayer membrane experiments
for model compounds. We showed that the enhanced permeability of the
short ceramides is mainly caused by the disturbance of their headgroup
conformation because of their inability to accommodate the shorter
lipid acyl chain into a typical hairpin conformation, which further
led to their destabilization and phase separation. As MD simulations
described well delicate structural features of SC membranes, they
seem to be suitable for further studies of the SC superstructure,
including the development of skin penetration enhancers for transdermal
drug delivery and skin toxicity risk assessment studies.