%-------------------------------------------
% Text S3. Simulate and plot figure 4.
%-------------------------------------------

%-------------------------------------------
% File name: plot_figure4.m
%-------------------------------------------
% author: Sohyoung Kim
% last updated: Jul-24-2009
% matlab 7.2.0.232 (R2006a) was used.
% Description: this script generates figure 4
%-------------------------------------------

%-------------------------------------------
% requirement to run this script.
%-------------------------------------------
% - need function definition file under current working directory: 
%       mdmx_p53_mdm2_model.m
%       base_params_early_respose.m
% - need directory p53act_mdm2var_mdmxeffect_more_data or make one.
%-------------------------------------------

% uncomment the following line if the directory has not been created.
%!mkdir p53act_mdm2var_mdmxeffect_more_data

clear;

% intialize params for early response.
base_params_early_respose; % load params var.

% initial condition
x0=zeros(14,1);
x0(13)=1; % max promoter limit.

% range of basal production rate for Mdm2.
k6s=logspace(-3,0,50);

% range of 
k_3_8_17_s=logspace(-3, .7, 40);

% index for phosphorylation/dephsophorylation rate, Mdm2, MdmX basal
% production rate.
phospho_ind=[3,8,17];
dephospho_ind=[4,9,18];
mdm_basal_prod_ind=6;
mdmx_basal_prod_ind=15;

%------------------------------------------
% simulation of no MdmX in the system.
%------------------------------------------
params(mdmx_basal_prod_ind)=0;

options=[];
for i=1:length(k6s), % loop to itereate various Mdm2 production rate.
    %---------------------------
    % simulate normal conditions
    %---------------------------    
    params(phospho_ind)=0; % no phosphorylation.
    params(mdm_basal_prod_ind)=k6s(i);                
    [x1, y1]=ode15s('mdmx_p53_mdm2_model',[0 500000], x0, options, params);
    
    for j=1:length(k_3_8_17_s), % loop to itereate various phosphorylation rate.        
        params(phospho_ind)=k_3_8_17_s(j);        
                   
        [x2, y2]=ode15s('mdmx_p53_mdm2_model',[0 5], y1(length(x1),:), options, params);                
        [x3, y3]=ode15s('mdmx_p53_mdm2_model',[0 50], y2(length(x2),:), options, params);                
        
        strfun=strcat('save p53act_mdm2var_mdmxeffect_more_data/mdmx0_sim_resulf_mdmx_p53_mdm2_model_i_', num2str(i), '_j_', num2str(j));                
        eval(strfun);        
    end;
end;

%------------------------------------------
% load data and plot figure.
%------------------------------------------
k_3_8_17_s=logspace(-3, .7, 40);

y1s1=[];
y1s2=[];
y1s3=[];

for i=1:length(k6s),    
    for j=1:length(k_3_8_17_s),                
        strfun=strcat('load p53act_mdm2var_mdmxeffect_more_data/mdmx0_sim_resulf_mdmx_p53_mdm2_model_i_', num2str(i), '_j_', num2str(j));                
        eval(strfun);                
        y1s1=[y1s1; y1(length(x1),:)];                
        y1s2=[y1s2; y2(length(x2),:)];                
        y1s3=[y1s3; y3(length(x3),:)];                
    end;
end;

p53_activity_ind=14;
ry1=reshape(y1s1(:,p53_activity_ind), 40, 50);
ry2=reshape(y1s2(:,p53_activity_ind), 40, 50);
ry3_0=reshape(y1s3(:,p53_activity_ind), 40, 50);

% plot figure 4-A
figure;
semilogx(k_3_8_17_s, ry3_0(:,1:8:50)', '-', 'LineWidth', 2);
set(gca, 'XTickLabel', [], 'YTickLabel', [])
axis([0 5 0 1]);
legend('0.001','0.003','0.0095','0.0295','0.091', '0.28','0.87');

% plot figure 4-B
figure; semilogx(k6s, ry3_0(1:6:40,:), '-', 'LineWidth', 2)
set(gca, 'XTickLabel', [], 'YTickLabel', [])
axis([10^-3 10^0 0 1]);
legend('0.001','0.0037','0.0138','0.051','0.189', '0.7','2.6');

ylabel('p53 activity (promoter occupancy by p53 tetramer)');
xlabel('Rate of Mdm2 basal production')
title({'Mdm2 dependency of p53 during early DNA damage response','with various levels of DNA damage'})

% End of script for Figure 4-A,B.

%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
% Generate data for Figure 4-C,D, and plot figures.
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%


clear;

% intialize params for early response.
base_params_early_respose; % load params var.

% initial condition
x0=zeros(14,1);
x0(13)=1; % max promoter limit.

% range of basal production rate for Mdm2.
k6s=logspace(-3,0,50);

% range of 
k_3_8_17_s=logspace(-3, .7, 40);

% index for phosphorylation/dephsophorylation rate, Mdm2, MdmX basal
% production rate.
phospho_ind=[3,8,17];
dephospho_ind=[4,9,18];
mdm_basal_prod_ind=6;
mdmx_basal_prod_ind=15;

%------------------------------------------
% simulation of no MdmX in the system.
%------------------------------------------
params(mdmx_basal_prod_ind)=0.05;

options=[];
for i=1:length(k6s), % loop to itereate various Mdm2 production rate.
    %---------------------------
    % simulate normal conditions
    %---------------------------    
    params(phospho_ind)=0; % no phosphorylation.
    params(mdm_basal_prod_ind)=k6s(i);                
    [x1, y1]=ode15s('mdmx_p53_mdm2_model',[0 500000], x0, options, params);
    
    for j=1:length(k_3_8_17_s), % loop to itereate various phosphorylation rate.        
        params(phospho_ind)=k_3_8_17_s(j);        
                   
        [x2, y2]=ode15s('mdmx_p53_mdm2_model',[0 5], y1(length(x1),:), options, params);                
        [x3, y3]=ode15s('mdmx_p53_mdm2_model',[0 50], y2(length(x2),:), options, params);                
        
        strfun=strcat('save p53act_mdm2var_mdmxeffect_more_data/mdmx05_sim_resulf_mdmx_p53_mdm2_model_i_', num2str(i), '_j_', num2str(j));                
        eval(strfun);        
    end;
end;

%------------------------------------------
% load data and plot figure.
%------------------------------------------
k_3_8_17_s=logspace(-3, .7, 40);

y1s1=[];
y1s2=[];
y1s3=[];

for i=1:length(k6s),    
    for j=1:length(k_3_8_17_s),                
        strfun=strcat('load p53act_mdm2var_mdmxeffect_more_data/mdmx05_sim_resulf_mdmx_p53_mdm2_model_i_', num2str(i), '_j_', num2str(j));                
        eval(strfun);                
        y1s1=[y1s1; y1(length(x1),:)];                
        y1s2=[y1s2; y2(length(x2),:)];                
        y1s3=[y1s3; y3(length(x3),:)];                
    end;
end;

p53_activity_ind=14;
ry1_05=reshape(y1s1(:,p53_activity_ind), 40, 50);
ry2_05=reshape(y1s2(:,p53_activity_ind), 40, 50);
ry3_05=reshape(y1s3(:,p53_activity_ind), 40, 50);

% plot figure 4-C
figure;
semilogx(k_3_8_17_s, ry3_05(:,1:8:50)', '-', 'LineWidth', 2, 'MarkerSize', 10);
% plot figure 4-D
figure; semilogx(k6s, ry3_05(1:5:40,:), '-', 'LineWidth', 2, 'MarkerSize', 10)

ylabel('p53 activity (promoter occupancy by p53 tetramer)');
xlabel('Rate of Mdm2 basal production')
title({'Mdm2 dependency of p53 during early DNA damage response','with various levels of DNA damage'})



% End of script for Figure 4-C,D.

%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
% Generate data for Figure 4-E,F, and plot figures.
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%


clear;

% intialize params for early response.
base_params_early_respose; % load params var.

% initial condition
x0=zeros(14,1);
x0(13)=1; % max promoter limit.

% range of basal production rate for Mdm2.
k6s=logspace(-3,0,50);

% range of 
k_3_8_17_s=logspace(-3, .7, 40);

% index for phosphorylation/dephsophorylation rate, Mdm2, MdmX basal
% production rate.
phospho_ind=[3,8,17];
dephospho_ind=[4,9,18];
mdm_basal_prod_ind=6;
mdmx_basal_prod_ind=15;

%------------------------------------------
% simulation of no MdmX in the system.
%------------------------------------------
params(mdmx_basal_prod_ind)=5;

options=[];
for i=1:length(k6s), % loop to itereate various Mdm2 production rate.
    %---------------------------
    % simulate normal conditions
    %---------------------------    
    params(phospho_ind)=0; % no phosphorylation.
    params(mdm_basal_prod_ind)=k6s(i);                
    [x1, y1]=ode15s('mdmx_p53_mdm2_model',[0 500000], x0, options, params);
    
    for j=1:length(k_3_8_17_s), % loop to itereate various phosphorylation rate.        
        params(phospho_ind)=k_3_8_17_s(j);        
                   
        [x2, y2]=ode15s('mdmx_p53_mdm2_model',[0 5], y1(length(x1),:), options, params);                
        [x3, y3]=ode15s('mdmx_p53_mdm2_model',[0 50], y2(length(x2),:), options, params);                
        
        strfun=strcat('save p53act_mdm2var_mdmxeffect/mdmx5_sim_resulf_mdmx_p53_mdm2_model_i_', num2str(i), '_j_', num2str(j));                
        eval(strfun);        
    end;
end;

%------------------------------------------
% load data and plot figure.
%------------------------------------------
k_3_8_17_s=logspace(-3, .7, 40);

y1s1=[];
y1s2=[];
y1s3=[];

for i=1:length(k6s),    
    for j=1:length(k_3_8_17_s),                
        strfun=strcat('load p53act_mdm2var_mdmxeffect_more_data/mdmx05_sim_resulf_mdmx_p53_mdm2_model_i_', num2str(i), '_j_', num2str(j));                
        eval(strfun);                
        y1s1=[y1s1; y1(length(x1),:)];                
        y1s2=[y1s2; y2(length(x2),:)];                
        y1s3=[y1s3; y3(length(x3),:)];                
    end;
end;

p53_activity_ind=14;
ry1_5=reshape(y1s1(:,p53_activity_ind), 40, 50);
ry2_5=reshape(y1s2(:,p53_activity_ind), 40, 50);
ry3_5=reshape(y1s3(:,p53_activity_ind), 40, 50);

% plot figure 4-E
figure;
semilogx(k_3_8_17_s, ry3_5(:,1:8:50)', '-', 'LineWidth', 2);
set(gca, 'XTickLabel', [], 'YTickLabel', [])
axis([0 5 0 1]);
legend('0.001','0.003','0.0095','0.0295','0.091', '0.28','0.87');

% plot figure 4-F
figure; semilogx(k6s, ry3_5(1:6:40,:), '-', 'LineWidth', 2)
set(gca, 'XTickLabel', [], 'YTickLabel', [])
axis([10^-3 10^0 0 1]);
legend('0.001','0.0037','0.0138','0.051','0.189', '0.7','2.6');

ylabel('p53 activity (promoter occupancy by p53 tetramer)');
xlabel('Rate of Mdm2 basal production')