Penetration of Gold Nanoparticle through Human Skin: Unraveling Its Mechanisms at the Molecular Scale

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1 Penetration of Gold Nanoparticle through Human Skin: Unraveling Its Mechanisms at the Molecular Scale Rakesh Gupta and Beena Rai* TATA Research Development & Design Centre, TCS Innovation labs, Pune India, *Corresponding author: Fax: Tel: Supplementary Information S1 Projected area on XY plane and Order parameter In a molecular dynamics simulation of lipid bilayer, which has normal along the z direction, the projected area on XY plane can be calculated using the following equation: A = 2 Lx Ly Nlipid Where Lx, Ly is the box length in X and Y direction, respectively and N is total number of lipid lipids in the bilayer. The second rank order parameter for the bilayer, which has normal in z direction, could be defined as: Sz = 1 2 (3cos2 θ 1) (2) where θ is the angle between the bond and the bilayer normal. Sz = 1 means perfect alignment with the bilayer normal, Sz = 0.5 anti-alignment, and Sz = 0 random orientation of the lipid chains. (1) S1

2 S2. Projected area on XY plane and overall order parameter along the bilayer axis Z Figure S2 shows the overall order parameter (S) of ceramide chains calculated in each window of 100 ns constrained simulation of AuNP s of different size. The overall order parameter was calculated using following relationship: S = n i=1 Sz(i) n Where n is number of beads in the ceramide molecules and Sz is order parameter for i th bead of ceramide chain as shown in the figure 1. (3) Figure S1: The projected area on XY plane calculated in each window of 100 ns constrained simulation of AuNP s of different size. Here z=0 correspond to the bilayer centre. Bilayers were assumed to be symmetric and profile in one leaflet (upper) was replicated in another leaflet. S2

3 Figure S2: Over all order parameter of ceramide chains in mixed 1:1:1 (CER: CHOL: FFA) bilayer system in presence of constrained AuNP s of size of 2nm, 3nm, 4nm, 5nm and 6 nm calculated in each window of 100 ns constrained simulation. Chain sn1 and sn2 are shown in the figure 1. For colour code refer to web version of the article. S3

4 S3. Convergence of free energy profiles Figure S3: Convergence of Potential of mean force (dg) of AuNP s of size of 3nm, 4nm, 5nm and 6 nm along the bilayer normal (Z) calculated from constrained CG MD simulation. Here z=0 correspond to the bilayer centre. Bilayers were assumed to be symmetric and profile in one leaflet (upper) was replicated in another leaflet. For colour code refer to web version of the article. S4

5 S4. Order parameter script The order parameter script is attached with the supplementary information. S5. Relationship between number of Gold atoms and free energy of permeation. Table S1. The free energy of permeation in the middle of the bilayer and number of atoms in each nanoparticle. Nanoparticle Number of Number of dg Size (nm) atoms N total surface atoms (kj/mol) dg/ N total dg/ N surface N surface ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± Figure S4: Dependence of free energy of permeation in the middle of the bilayer on the number of surface and total number of atom of gold nanoparticle (left). Dependence of Free energy per atom of gold nanoparticle on the number of surface and total atom of gold nanoparticle (Right). S5

6 S6. Effect of undulation on the bilayer free energy profile. The free energy in the bulk and in the interior are almost symmetric, but in the middle of the bilayer we have not observed the symmetric nature. The free energy decreases little bit more when the AuNP moves downwards from the middle of the bilayer. The possible mechanism could be that the AuNP is fully covered by the CHOL, FFA and CER and there is no contact with water which reduces the free energy. Though results of permeation was not changed significantly since the main resistance of the permeation was found to be in water and head group-water interface. Figure S5. Effect of undulation on the free energy of permeation of 5nm AuNP through skin lipid bilayer. S6

7 S7. Effect of surface morphology of gold nanoparticle on the skin lipid bilayer. Figure S6. AuNP of size of 2.2 nm with two different surface morphology b) and c) Interaction of 2.2 nm AuNP with mixed 1:1:1 (CER: CHOL: FFA) bilayer. Structural changes induced by the AuNP in the bilayer with simulation time. Water molecules were removed for the purpose of clarity. Images/snapshots were created using the VMD software 1. S7

8 To check the effect of surface morphology of gold nanoparticle over bilayer properties, additional simulation of 2.2 nm gold nanoparticle of two different surfaces (similar to Lin et al. 2-4 and generated from nanoparticle builder 5 ) have been carried. Lin et al. 2-4 surface and nanoparticle builder 5 surface are named as case 1 and case 2 respectively. These simulation were run for 1 µs. The order parameter, projected area on XY plane and structural properties are shown below. The projected area on XY plane gives a qualitative picture of the bilayer curvature. A lower projected area will be correspond to the more of curvature or undulation in the bilayer. Projected area on XY Plane was for case 1 and case 2 was found to be ± nm 2 and ± nm 2 respectively. Also the order parameter profile was also found to be similar. Figure S7. Tail order parameter of CER chain sn1 and sn2 in mixed 1:1:1 (CER: CHOL: FFA) bilayer for two cases. The chain sn1 and sn2 are and corresponding bead numbers are shown in figure 1. For color code refer to web version of the article. S8

9 S8. AuNP permeation from ceramide and DPPC bilayer. a) b) c) Figure S8. Interaction of 2nm AuNP with a) CER and b) DPPC bilayer. Water molecules were removed for the purpose of clarity. Images/snapshots were created using the VMD software 1. c) Distance between the center of mass of AuNP and lipid bilayer with the simulation time. To see the effect of AuNP over phospho and sphingo lipids, additional simulation of DPPC and CER bilayer performed in the presence of 2nm AuNP. The parameter for the DPPC bilayer were taken from the MARTINI force field ( 6,7 The coarse grained parameters for CER were taken from the recent work of Sovova et al. 8 The snapshots of the simulation and the time taken for permeation are shown above. Time taken by the AuNP to reach inside the DPPC bilayer was little bit smaller as compared to S9

10 CER bilayer. Also AuNP penetrated deeper in the interior of the DPPC bilayer as compared to CER bilayer. S10. Area per lipid and bilayer thickness calculated from tool. The area per lipid and bilayer thickness calculated using the tool 9 are shown in the figure S11. The area per lipid values decreases with increase in the AuNP size, whereas bilayer thickness increases with the AuNP size. Figure S9. The 2d graph of area per lipid distribution in each bilayer system calculated using tool 9. S10

11 Figure S10. Area per lipid (left) and bilayer thickness (right) in each bilayer system calculated using tool 9. Reference 1. Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual Molecular Dynamics. J. Mol. Graph. 1996, 14(1), Lin, J. Q.; Zheng, Y. G.; Zhang, H. W.; Chen, Z. A Simulation Study on Nanoscale Holes Generated by Gold Nanoparticles on Negative Lipid Bilayers. Langmuir 2011, 27(13), Lin, J.; Zhang, H.; Chen, Z.; Zheng, Y. Penetration of Lipid Membranes by Gold Nanoparticles: Insights Into Cellular Uptake, Cytotoxicity, and Their Relationship. ACS Nano 2010, 4(9), Lin, J. Q.; Zhang, H. W.; Chen, Z.; Zheng, Y. G.; Zhang, Z. Q.; Ye, H. F. Simulation Study of Aggregations of Monolayer Protected Gold Nanoparticles in Solvents. J. Phys. Chem. C 2011, 115(39), S11

12 5. Gezelter, J.D.; Kuang, S.; Marr, J.; Stocker, K.; Li, C.; Vardeman, C.F.; Lin. T.; Fennell, C.J.; Sun, X.; Daily, K; Zheng, Y. OpenMD, an Open source Engine for Molecular Dynamics. (accessed August 23, 2015) 6. Marrink, S. J.; De Vries, A. H.; Mark, A. E. Coarse Grained Model for Semiquantitative Lipid Simulations. J. Phys. Chem. B 2004, 108(2), Marrink, S. J.; Risselada, H. J.; Yefimov, S.; Tieleman, D. P.; De Vries, A. H. The MARTINI Force Field: Coarse Grained Model for Biomolecular Simulations. J. Phys. Chem. B 2007, 111(27), Sovova, Z.; Berka, K.; Otyepka, M.; Jurecka, P. Coarse-Grain Simulations of Skin Ceramide NS with Newly Derived Parameters Clarify Structure of Melted Phase. J. Phys. Chem. B 2015, 119(10), Lukat, G.; Kru ger, J.; Sommer, B. APL@ Voro: A Voronoi Based Membrane Analysis Tool for GROMACS Trajectories. J. Chem. Inf. Model. 2013, 53(11), S12