Experimental evidence-based atomistic model for stratum corneum lipid matrix for skin permeation studies
The 3D structures of ceramide NP, ceramide AP, lignoceric acid and water generated using ‘3D Builder’ of Schrodinger Maestro 2021.3 are in the folder model_building/initial_structures.
The input file of Packmol v18.169 is model_building/pack_model.inp.
packmol < pack_model.inp
The output structure of Packmol is model_building/sc_box_070070080_2jun22.pdb.
sc_box_070070080_2jun22.pdb was converted to .gro fromat and the residues were renumbered.
gmx editconf -f sc_box_070070080_2jun22.pdb -o sc_box_070070080_2jun22.gro -bt triclinic -box 7 7 8
model_building/sc_box_renumbered.gro was the starting structure for MD_simulation.
The CHARMM36 parameter files of the molecules are in charmm36_parameters.
The shell scripts and .mdp files used for equilibrating the model are in model_equilibration. The scripts were run in the following order.
./em.sh
./nvt_eq.sh
./npt_eq.sh
./npt_eq_8.sh
./npt_prod.sh
The initial structure of production simulation is Model_Structure_npt_eq_8_5.pdb.
Lengths of the simulation box in XY and Z dimensions for calculation of periodicity and area per ceramide was obtained using the following command.
gmx energy -f npt_prod_1-3.edr -o Box_XYZ.xvg
The densities of system coomponents along Z-axis was calculated using the following command.
gmx density -f npt_prod_1-3.trr -s npt_prod_1.tpr -o densities/all_1-3.xvg -center -relative -symm -ng 6 -sl 75
The angle between the fatty acid tails and sphingosine tails of ceramides were calculated using system_properties/angle_ceramide_ext.ipynb.
For calculating NSLD plots using SIMtoEXP, the number densities of C, H, O and N atoms along z-axis was calculated using the following command.
gmx density -f npt_prod_1-3.trr -s npt_prod_1.tpr -o densities/chon_1-3.xvg -n indices/chon.ndx -center -sl 400 -ng 4 -dens number
The input files used in SIMtoEXP to generate the NSLD plots for the simulated models are system_properties/extended_ceramide.sim and system_properties/hairpin_ceramide.sim.
The experimental NSLD plots from Groen et al (Figure 4A in https://doi.org/10.1016/j.bpj.2011.02.001) and Schmitt et al (Figure 3A (dashed line) in https://doi.org/10.1021/acs.langmuir.7b01848) were read using the MATLAB code at https://www.mathworks.com/matlabcentral/fileexchange/7173-grabit (Accessed January 24, 2024).
The NSLD values and the python script used for plotting Figure 9 in the manuscript are system_properties/NSLD.csv and system_properties/nsld.ipynb.
The shell scripts and .mdp files used for the MD simulations performed for analyzing the effect of addition of 10 wt% and 20 wt% water are in hydration_simulations.
Water molecules were inserted into the system using hydration_simulations/insert_water.sh.
The simulation scripts were run in the following order.
./em.sh
./nvt_eq.sh
./npt_eq.sh
./npt_prod.sh
The shell scripts and .mdp files used for the Steered MD simulations performed for analyzing the permeability of water, benzene and estradiol are in umbrella_sampling.
Permeants were inserted into the system using umbrella_sampling/insert.sh.
Short equilibration after insertion of permeants were performed running the scripts in the following order.
./em.sh
./nvt_eq.sh
./npt_eq.sh
The Steered MD simulatins were perfomed using umbrella_sampling/pulling.sh and umbrella_sampling/pulling.mdp.
The frames were extracted from Steered MD trajectory at regular intervals using umbrella_sampling/extract_frames_v2.pl for performing umbrella sampling.
Umbrella sampling simulatins were perfomed using umbrella_sampling/us/us.pl and umbrella_sampling/us/us.mdp.
The PMF profiles were calculated using umbrella_sampling/us/wham.sh.
The dG associated with the transfer of permeant from bulk water to stratum corneum lipid matrix was calculated using umbrella_sampling/us/dG_transfer_FEP/run.sh.
The position autocorrelation functions required for deriving the diffusion coefficients were calculated using umbrella_sampling/us/xacf20.pl.
The folder permeability_calculation_scripts contains the MATLAB scripts used for calculation of Permeability Coefficient from PMF and Diffusion Coefficients using Inhomogeneous Solubility Diffusion Model.
The shell scripts and .mdp files used for the MD simulations performed for analyzing the effect of addition of 5 wt% and 10 wt% of permeation enhancers are in permeation_enhancer_simulations.
Permeation enhancer molecules were inserted into the system using permeation_enhancer_simulations/insert_PE.sh.
The simulation scripts were run in the following order.
./em.sh
./nvt_eq.sh
./npt_eq.sh
./npt_prod.sh