Molecular Structure of the Long Periodicity Phase in the Stratum Corneum

Abstract

The long periodicity phase (LPP) of the stratum corneum (SC) is studied using all-atom molecular dynamics simulations of sandwich models on the microsecond timescale. The interior of the sandwich structure is fluid but transitions into the gel phase due to free fatty acid (FFA). Ceramides (Cer) transition from hairpin to extended conformations, and the mechanism is characterized by initial anchoring of the head-proximal carbons. FFA translocates through the interior on the hundred-nanosecond timescale, and cholesterol (Chol) is oriented perpendicular to the normal at the bilayer-monolayer interface. Strong agreement with experiment is noted based on electron density and neutron scattering length density (NSLD), and the high disorder of Cer linoleate supports infrared spectroscopy. Cer preferentially clusters over Chol and FFA in the outer leaflet. To further validate the model, ethanol permeability was calculated using umbrella sampling, which agrees excellently with experiment (logP of −6.5 cm/s vs. −6.7 cm/s in experiment) and suggests that the limiting factor is the LPP. Furthermore, a leapfrog mechanism of ethanol permeation into the skin is proposed. These are the first experimentally verified sandwich models of the LPP and will aid the design and optimization of transdermal drug delivery systems.