Molecular Structure of the Long Periodicity Phase in the Stratum Corneum.

All-atom models of the long periodicity phase (LPP) in the stratum corneum (SC) are studied using bilayer-slab-bilayer (sandwich) structures and multi-microsecond simulations. Linoleate promotes melting of the interior slab, which contains ceramide (Cer) in the posturing chain conformation, a structurally distinct conformation from full chain extension. The mechanism of Cer transitioning into full extension is characterized by initial anchoring of the head-proximal carbons and occurs over tens of nanoseconds. Free fatty acids translocate through the interior over hundreds of nanoseconds, while Cer and cholesterol take around a microsecond or longer to translocate. Electron density and neutron scattering length density profiles from simulation agree with experiment, and the high disorder of linoleate in CerEOS supports experiments with infrared spectroscopy and nuclear magnetic resonance. Lateral organization demonstrates dependence on lipid composition and bilayer thickness. To further validate the LPP model, umbrella sampling was used to calculate ethanol permeability in comparison with experiment (log(P) values obtained from modeling the SC's multiple LPP layers are -7.6 and -6.6 cm/s, and that from experiment on cadaver skin is -6.65 cm/s). A "leapfrog" mechanism for ethanol permeation is proposed which is associated with its role as a topical enhancer. These models, the first experimentally verified atomistic sandwich models of the LPP, will aid in the design and optimization of transdermal drug delivery.