Tutorial 8

In-Silico Skin Model – A molecular model for the top layer (Stratum Corneum) of human skin

This tutorial demonstrates the "newatom" and "info" keywords.

Introduction

Transdermal delivery of therapeutic drugs have been looked upon as one of the most efficient routes for targeted drug delivery in humans. Traditionally the pharmaceutical industry has majorly relied upon, in-vitro and in-vivo trials carried on animals to come up with a suitable formulation of the drug. With the recent ban on animal testing in many countries, the community has shifted to synthetic (cell-cultured) skin to test their hypothesis. However, this experimental route has proven to be extremely costly and time consuming at the same time. Thus, we propose an in-silico skin model, wherein we have built a multiscale model for the topmost layer of the human skin- the Stratum Corneum. At the microscopic level, the molecular dynamics(MD) based model takes into consideration the chemical composition of the stratum-corneum (cholesterol, fatty acids and ceramides) to accurately replicate its chemical nature, while at the macroscopic level, the finite element model(FEM) mathematically describes the physical brick and mortar structure of the lipid matrix and corneocytes.

Here we are presenting the case studies on using gold nanoparticle in the transdermal drug delivery application. The skin’s top layer (stratum corneum) provide a barrier and in order to deliver drugs or protein it has to be breached. The gold nanoparticle is used as a breaching agent and it is shown that it can deliver protein in the skin. The in-silico skin model unravels a myriad of phenomenon taking place at the microscopic level which shall help the transdermal drug delivery research to expedite their effort at the same time having substantial monetary benefits. 

Dataset

This module will show the use of gold nanoparticle in the transdermal drug delivery application. The in-silico skin model of lipid bilayer is made up of ceramide (CER), cholesterol (CHOL) and free fatty acid (FFA) as shown below (Fig 1).

Figure 1: Ceramides, Cholesterol, Free Fatty Acid and HRP (Schematic) Figure 2: Ceramides, Cholesterol, Free Fatty Acid and HRP (Virtual Reality)

We begin with an xyz file skin.zip and a texture file for our infobox Gold.png. In organic chemistry, it is common that xyz files (for coarse grained simulations) contain special names for atoms or residues. Some chemical symbols may also be adapted for a different compound.

In coarse grained (CG) model, three or four atoms are clubbed together as a bead as shown in Fig 1. Skin lipid molecules have two parts namely head and tail group. The polar part (having N, O and polar H) are head groups and nonpolar long aliphatic/aromatic carbon chains are tail groups. The CER has two tails sn1 and sn2 (T1x and T2x beads), FFA has only one chain (CxA beads) and CHOL have bulky aromatic groups (Rx beads) and small aliphatic chain (Cx beads).  The CER has big head groups having three beads (Hx), Each FFA and CHOL has small head group with HE1 and ROH bead respectively.

Skin.zip contains the combined trajectory of three separate coarse grained (CG) MD simulations. At first, the in silico skin model is created using self-assembly simulations and validated with experimental data. The delivery of protein through this model is attempted but as seen protein remains adsorbed on the surface of the skin lipid bilayer. To deliver this protein, we need some kind of carrier which could disturb the barrier. The gold nanoparticle is tried and it was able to breach the barrier by creating pores inside the layer. Finally, both protein and gold nanoparticle were used together and both were able to penetrate the barrier. At first, protein binds to the gold nanoparticle and then particle creates the pore (voids) by redistribution of lipids and finally takes protein into the deeper layer.

References

  • Rakesh Gupta, D Sridhar and Beena Rai. METHOD AND SYSTEM FOR TESTING OF ACTIVE MOLECULES USING MOLECULAR SIMULATION OF SKIN MEMBRANE. Filed on March 20, 2017. Application number EP17161819.2
  • Rakesh Gupta, Kishore Gaujla, D Sridhar and Beena Rai.METHOD AND SYSTEM FOR IN-SILICO TESTING OF ACTIVES ON HUMAN SKIN. Filing Jurisdiction: EPO. Application Number: 18155772.9-1111
  • Gupta, Rakesh, and Beena Rai. "Penetration of Gold Nanoparticles through Human Skin: Unraveling Its Mechanisms at the Molecular Scale." The Journal of Physical Chemistry B120, no. 29 (2016): 7133-7142.
  • Rakesh Gupta, Nishi Kashyap and Beena Rai, Transdermal Cellular Membrane Penetration of Protein with Gold Nanoparticle: A Molecular Dynamics Study, RSC PCPP, 2017, DOI: 10.1039/C6CP08775B
  • Rakesh Gupta and Beena Rai, Molecular Dynamics Simulation Study of Translocation of Fullerene C60 through Skin Bilayer: Effect of Concentration over Barrier Properties. RSC NANOSCALE.2017. DOI: 10.1039/C6NR09186E
  • Rakesh Gupta and Beena Rai, Effect of Size and Surface Charge of Gold Nanoparticles on their Skin Permeability: A Molecular Dynamics Study, Nature Scientific Reports. 2017.
  • Gupta, R., Kashyap, N. and Rai, B., 2017. Molecular mechanism of transdermal co-delivery of interferon-alpha protein with gold nanoparticle–a molecular dynamics study. Molecular Simulation, pp.1-11.
  • Gajula, K., Gupta, R., Sridhar, D.B. and Rai, B., 2017. In-Silico Skin Model: A Multiscale Simulation Study of Drug Transport. Journal of Chemical Information and Modeling57(8), pp.2027-2034.
  • Gupta, R. and Rai, B., 2018. In-silico design of nanoparticles for transdermal drug delivery application.Nanoscale, 10(10), pp.4940-4951

Bead information

Our example file contains the following symbols (the size of the beads is in Ångström):

Ceramide:
H: Head group beads (H1, H2 and H3, radius 3.6)
T : Tail group beads (T11, T12...,T1x, T21, T22.....T2x, radius 2.6)

Cholesterol:
ROH : Head group bead (Rings with -OH group, radius 2.3)
R: Tail group beads (bulky aromatic rings, R1, R2, ....Rx, size 2.3)
C: Tail group beads (small aliphatic chains, C1, C2, ...Cx, size 2.3)

Free Fatty Acid:
HE1 : Head group bead (radius 2.6)
C1A - C5A, C5B : Tails group beads (radius 2.6)

Protein:
BB: Backbone bead (radius 2.6)
SC: Side chain bead (radius 2.6)

Configuration file

For representation purposes, we want to de-emphasize T (normal size 2.6, becomes 1.5), R (normal size 2.3, becomes 1.3) and C1A-C5A, C6B (normal size 2.6, becomes 1.6). We also choose the desired colour for each bead type.
The configuration option is

newatom <Symbol> <Red> <Green> <Blue> <Radius>

and in our case:

newatom BB 1 0.5 1.0 2.6
newatom SC 0.1 0 0.1 2.6
newatom T 1 0 0 1.5
newatom H 0.2 1 1 3.6
newatom ROH 0 1 0 1.3
newatom R 0 1 0 1.3
newatom C 0 1 0 1.3
newatom HE 0.2 1 1 2.6
newatom C1A 0 0 1 1.6
newatom C2A 0 0 1 1.6
newatom C3A 0 0 1 1.6
newatom C4A 0 0 1 1.6
newatom C5A 0 0 1 1.6
newatom C6B 0 0 1 1.6

Visualization on HTC Vive

Addition of information boxes

Information boxes have the following format:

info <X> <Y> <Z> <Size> <Particle Number> <Texture>

The lines are then:

info 90 30 150 10 26554 "Gold.png"
infolinecolour 1 0 0
menubutton Infobox

Changing the clipping planes

Since this is a spatially large simulation, we change the clipping planes:

clippingplanes 0.2 400

Final configuration file

skin.ncfg

Thanks

The simulation was performed by Gupta Rakesh from TATA Consultancy Services, who also provided the diagram above.