Simulation code and instructions from A model-based analysis of tissue targeting efficacy of nanoparticles

The compressed folder, model.tar.gz, contains C++ source files. In addition, README.txt file is provided in the folder with instructions to compile the code and execute simulation

LAT dephosphorylation in the simulated hapten-inhibition experiment.

<p>Lines represent the simulation results, and symbols represent the experimental data of Peirce and Metzger <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669-Peirce1" target="_blank">[40]</a>. Different lines in panels A and B represent different levels of raft protection as indicated by the parameter Experimental data and the line at in panel A are re-plotted in linear scale in panel C. Experimental data and the line at in panel B are re-plotted in linear scale in panel D. The top and the bottom panels represent different values of the receptor-Syk dissociation constant in the model: The value taken from Faeder et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669-Faeder1" target="_blank">[41]</a>, is used in panels A and C, and is used in panels B and D. In simulations, steady-state receptor crossliking is induced with a bivalent ligand concentration of 1 nM, and then monovalent hapten is added at 100 µM (Materials and Methods). Time zero indicates the point when hapten is added. In simulations, default values (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669.s005" target="_blank">Table S1</a>) are used for parameters not shown in the figure.</p

Effects of raft lifetime decrease on dephosphorylation kinetics.

<p>The hapten inhibition experiment is simulated with a mean raft lifetime s (instead of 10 s, the default value in the model). With this change in the lumped parameter (Eq (1)) is adjusted to keep the partition coefficients of proteins fixed. For other parameters, default values (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669.s005" target="_blank">Table S1</a>) are used. Dephosphorylation kinetics of FcεRI β and γ are shown in panel A and B, respectively. Dephosphorylation kinetics of Syk and LAT are shown in panel C and D, respectively.</p

Effects of Lyn palmitoylation mutation on protein phosphorylation.

<p>Simulation results are compared with experimental data of Kovarova et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669-Kovarova1" target="_blank">[29]</a>. In the figure, WT represents wild type Lyn, and CA represents palmitoylation-mutated Lyn. Letter M within parentheses represent model predictions and E represents experimental data. Simulation results presented are for a fixed level of raft protection corresponding to . Default values are used for other parameters, as listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669.s005" target="_blank">Table S1</a>.</p

Binding and phosphorylation reactions in the model that occur both in raft and in nonraft compartments.

<p>1) Constitutive association of Lyn unique domain with the β subunit of the receptor. 2) Binding and cross-linking of IgE-FcεRI complexes by a multivalent ligand; 3) Transphosphorylation of the β and γ ITAMs by constitutively associated Lyn. 4) Recruitment of Lyn through its SH2 domain to the phosphorlated β ITAM and recruitment of Syk through its two SH2 domains to the doubly phosphorylated γ ITAM. 5) Michaelis-Menton interaction of a receptor aggregate containing Syk with LAT resulting in a phosphorylated LAT. 6) Binding of Grb2 to phosphorylated. Not shown are the reactions that dephosphorylate unprotected tyrosines.</p

FcεRI and LAT dephosphorylation in the hapten-inhibition experiment of Peirce and Metzger [40].

<p>The figure is modified from Fig. 4B in Peirce and Metzger <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669-Peirce1" target="_blank">[40]</a>. Square symbols represent FcεRI and the circles represent LAT. The experiment is detailed in Peirce and Metzger <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669-Peirce1" target="_blank">[40]</a> and in Materials and Methods of this study. RBL cells were first stimulated with a polyvalent antigen to induce receptor crosslinking and signaling (before time zero in the figure), and then excess monovalent hapten was added (at time zero) to break up the receptor crosslinking. Subsequently, amounts of phosphorylated FcεRI and LAT were assayed at different time points. The figure shows the fraction of phosphorylated FcεRI and LAT remaining after hapten addition.</p

MOESM1 of A multiscale modeling study of particle size effects on the tissue penetration efficacy of drug-delivery nanoparticles

Additional file 1: Model Source Code. The compressed folder, S1_File.zip, contains necessary files and instructions to run a simulation. The file named main.cpp contains the C++ source code. The file named README.txt contains necessary instructions to compile the code and execute the simulation. (ZIP 8 kb

Concentration-dependent effects of APC constructs in SW480 cells.

<p>Predicted level is shown as a function of expression level for APC-B, -C, -D, and -E. In each panel, the represents the amount of expression relative to the endogeneous level of APC1338 (100 nM). The represents the level relative to the nominal level in a normal cell (35 nM, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003217#pcbi-1003217-t001" target="_blank">Table 1</a>). Thus, a value of 1 on the corresponds to a concentration of 100 nM of transfected protein, and a value of 1 on the corresponds to a concentration of 35 nM of . The simulation results shown here were obtained using BioNetGen input files provided in the Supporting Information: <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003217#pcbi.1003217.s006" target="_blank">Text S3</a> was used for panel A, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003217#pcbi.1003217.s008" target="_blank">Text S5</a> was used for panel B, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003217#pcbi.1003217.s009" target="_blank">Text S6</a> was used for panel C, and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003217#pcbi.1003217.s010" target="_blank">Text S7</a> was used for panel D.</p

Concentration-dependent effects of full-length APC on .

<p>(A) level in a normal cell is shown as a function of APC concentration. The represents the relative amount of APC introduced exogeneously with respect to the endogeneously present 100 nM of full-length APC in a normal cell. The represents the level of relative to its nominal level in a normal cell (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003217#pcbi-1003217-t001" target="_blank">Table 1</a>). (B) level in an SW480 cell is shown as a function of APC concentration. The represents the amount of APC introduced exogeneously relative to the endogeneously present 100 nM of APC1338 in an SW480 cell. The represents the level of relative to its nominal level in a normal cell, as in panel A. The simulation results shown here were obtained using BioNetGen input files provided in the Supporting Information: <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003217#pcbi.1003217.s005" target="_blank">Text S2</a> was used for panel A and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003217#pcbi.1003217.s007" target="_blank">Text S4</a> was used for panel B.</p

Effects of lipid raft lifetime increase on protein dephosphorylation.

<p>The hapten inhibition experiment is simulated with a mean raft lifetime s (instead of 10 s, the default value in the model). With this change in the lumped parameter (Eq (1)) is adjusted to keep the partition coefficients of proteins fixed. For other parameters, default values (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051669#pone.0051669.s005" target="_blank">Table S1</a>) are used. Dephosphorylation kinetics of FcεRI β and γ are shown in panel A and B, respectively. Dephosphorylation kinetics of Syk and LAT are shown in panel C and D, respectively.</p