Evaluation of Constrained and Restrained Molecular Dynamics Simulation Methods for Predicting Skin Lipid Permeability

Recently, molecular
dynamics (MD) simulations have been utilized
to investigate the barrier properties of human skin stratum corneum
(SC) lipid bilayers. Different MD methods and force fields have been
utilized, with predicted permeabilities varying by few orders of magnitude.
In this work, we compare constrained MD simulations with restrained
MD simulations to obtain the potential of the mean force and the diffusion
coefficient profile for the case of a water molecule permeating across
an SC lipid bilayer. Corresponding permeabilities of the simulated
lipid bilayer are calculated via the inhomogeneous solubility diffusion
model. Results show that both methods perform similarly, but restrained
MD simulations have proven to be the more robust approach for predicting
the potential of the mean force profile. Critical to both methods
are the sampling of the whole trans-bilayer axis and the following
symmetrization process. Re-analysis of the previously reported free
energy profiles showed that some of the discrepancies in the reported
permeability values is due to misquotation of units, while some are
due to the inaccurately obtained potential of the mean force. By using
the existing microscopic geometrical models via the intercellular
lipid pathway, the permeation through the whole SC is predicted from
the MD simulation results, and the predicted barrier properties have
been compared to experimental data from the literature with good agreement.