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

Area of Science:

• Biophysics
• Computational Chemistry
• Materials Science

Background:

• Molecular dynamics (MD) simulations are increasingly used to study human skin stratum corneum (SC) lipid bilayers.
• Variations in MD methods and force fields lead to significant discrepancies in predicted skin permeabilities.
• Understanding SC barrier properties is crucial for drug delivery and cosmetic formulations.

Purpose of the Study:

• To compare constrained versus restrained MD simulations for calculating water molecule permeation across SC lipid bilayers.
• To determine the most robust MD approach for obtaining potential of the mean force (PMF) and diffusion profiles.
• To refine permeability calculations and improve agreement with experimental data.

Main Methods:

• Constrained and restrained MD simulations were employed to model water permeation through an SC lipid bilayer.
• The inhomogeneous solubility diffusion model was used to calculate lipid bilayer permeabilities.
• Trans-bilayer axis sampling and symmetrization were critical steps in the analysis.
• Re-analysis of existing free energy profiles was performed to identify sources of error.

Main Results:

• Both constrained and restrained MD simulations yielded comparable results for PMF and diffusion profiles.
• Restrained MD simulations demonstrated superior robustness in predicting the PMF profile.
• Discrepancies in previous permeability values were attributed to unit misquotations and inaccurate PMF.
• MD simulation results, integrated with microscopic models, accurately predicted SC barrier properties.

Conclusions:

• Restrained MD simulations provide a reliable method for assessing SC lipid bilayer permeability.
• Accurate sampling and symmetrization are essential for valid MD-based barrier property predictions.
• This study refines MD simulation methodologies, enhancing their predictive power for skin barrier function.
• The findings offer improved insights into the biophysical mechanisms governing skin permeation.