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

Abstract

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.

Mechanisms of the Drug Penetration Enhancer Propylene Glycol Interacting with Skin Lipid Membranes

“…A decrease in bilayer thickness may correspond to increased interdigitation or disordering of lipid tails. For the pure water systems, the CHARMM bilayer thickness value of 4.89 ± 0.04 nm is in good agreement with that of Piasentin et al (4.90 ± 0.04 nm), and the UA bilayer thickness value of 4.71 ± 0.08 nm is in good agreement with that obtained by Del Regno and Notman (4.76 ± 0.3 nm). The bilayer thickness values for both pure water systems are close to the experimental value of 5.39 nm observed by Školová et al when studying an equimolar CER­[NS]/FA24/CHOL membrane at 330.15 K.…”

“…The APL gives insights into the packing of the lipid headgroups. The APL of the CHARMM bilayer solvated with pure water was calculated to be 0.325 ± 0.001 nm 2 , which is in good agreement with that obtained by Piasentin et al 54 (0.325 ± 0.002 nm 2 ), who also used the CHARMM36 force field to study an equimolar CER[NS]24/FA24/CHOL bilayer at 303.15 K, and the APL value of 0.307 ± 0.0003 nm 2 for the UA bilayer in pure water is in good agreement with that obtained from MD simulations by Del Regno and Notman 55 (0.304 ± 0.02 nm 2 ) using the same model bilayer at 305 K.…”

“…The AA and UA model SC bilayers used in this work were composed of CER­[NS]­24, FA24, and CHOL in an equimolar ratio. CER­[NS]­24 was selected as the main ceramide component since it is one of the most abundant and most studied ceramides, which enables comparison to extensive previous MD simulation work − using this lipid bilayer configuration.…”

“…Quantum mechanical calculations using ORCA 5.0 software 53 were carried out to obtain the energy profile for the O− C−C−O dihedral angle of PG. First, the geometry of PG was optimized at the RHF/def2-TZVP level.…”

Interactions between Rhodamine Dyes and Model Membrane Systems—Insights from Molecular Dynamics Simulations

“…The simple use of the thermodynamic relationship ∆G = −RTlnK P ⇔ K P = exp(−∆G/RT) (R and T being the gas constant and absolute temperature, respectively) is probably not valid, because of different underlying reference states in the experimental and calculated K P , as well as arbitrariness in establishing the water/lipid interphase in the simulations. Still, in a number of computational works, K P is taken as proportional to the integral of the exponential term along the reaction coordinate, thus accounting for both the depth and width of the free energy well [38][39][40][41][42]:…”