Qualitative, semi-quantitative, and quantitative simulation of the osmoregulation system in yeast

In this paper we demonstrate how Morven, a computational framework which can perform qualitative, semi-quantitative, and quantitative simulation of dynamical systems using the same model formalism, is applied to study the osmotic stress response pathway in yeast. First the Morven framework itself is briefly introduced in terms of the model formalism employed and output format. We then built a qualitative model for the biophysical process of the osmoregulation in yeast, and a global qualitative-level picture was obtained through qualitative simulation of this model. Furthermore, we constructed a Morven model based on existing quantitative model of the osmoregulation system. This model was then simulated qualitatively, semi-quantitatively, and quantitatively. The obtained simulation results are presented with an analysis. Finally the future development of the Morven framework for modelling the dynamic biological systems is discussed.


The JMorven Program File and User Manual
The JMorven program file JMorvenV1.1a.jar as well as some example model files are available for download at https://sites.google.com/site/jmorven/. A comprehensive user manual for JMorven, named MorvenManual.pdf, is also available for download at the same website.

Model Files for Reproducing Simulation Results
To reproduce the simulation results described in the manuscript, the user is suggested to first read the JMorven user manual. The relevant files used for simulation with JMorven are compressed into a zip file named Data.zip, which can be downloaded from https: //sites.google.com/site/jmorven/. After decompressing this zip file, a folder called Data will be created, and all relevant files for simulation are stored in this folder. You can load these files into JMorven and perform simulation according to the user manual.

The two-gene regulatory network
The two-gene regulatory network is shown in Figure 1 in the manuscript, and its JMorven model is given in Table 1. The model file for simulating this system is TwoGen SimpleQS.txt, and the quantity space file is simpleQS.txt. Both of these two files are in the subfolder Data/twoGenNetwork. To perform simulation (total and complete envisionment), simply load these two files into JMorven and follow the instruction from the user manual.

The qualitative model for the biophysical process of the osmoregulation
The qualitative model for the biophysical process of the osmoregulation is described in Section 4.1 of the manuscript, and the model and quantity space files are BioPhyOsmotic.txt and simpleQS.txt, both of which are located in the subfolder Data/OsmoticStressModel/ QulitativeModel/BiophysicalModel. To reproduce the results as shown in Figure 3 of the manuscript, load these two files and perform the total envisionment according to the user manual.

Qualitative simulation for the Gennemark simple model
To reproduce the complete envisionment shown in Figure 4 and Table 7 of the manuscript, we should load the model file OsmoticModel V&Gly.txt and the quantity space file Os-moticsimpleQS.txt, both of which can be found in the subfolder Data/OsmoticStressModel/ QulitativeModel/CompleteModel.

Quantitative and semi-quantitative simulation for the Gennemark simple model
To reproduce all the simulation results presented in Section 5 of the manuscript, we should use the model file OsmoticModel.txt and quantity space file OsmoticQSpaces.txt, both of which can be found in the subfolder Data/OsmoticStressModel/SemiQuantitativeModel. It is noted that the model and quantity space files are basically the same as those used for qualitative simulation. The only difference is that in qualitative simulation we may have different "printout" variables (variables to be shown in the envisionment), which are specified in the last line of the model file.

Quantitive simulation
To perform the quantitative simulation as shown in Figures 5 and 6 of the manuscript, after loading the model and quantity space files we should click the button "Select SemiQ Initial State" and load the initial values file Initial StateSemiQPe=0.558.txt, which is in the same subfolder as the model file (Data/OsmoticStressModel/SemiQuantitativeModel ). Parse the input files by clicking the "Parse Input Files" button. Then click "Simulate SemiQ" button, and in the popup windows set the time step size to be 0.01, the length of time to simulate over to be 120 (to make a quick simulation we can specify a shorter time period, say, 10), the simulation mode to be Basic Interval Simulation, and the integration mode to be Taylor Method. Perform the quantitative simulation and see the results obtained.

Semi-quantitative simulation I
To perform the semi-quantitative simulation as shown in Figure 7, we use the initial values file Initial SemiQPe=0.50-0.56.txt, which can be found in the folder Data/OsmoticStressModel/ SemiQuantitativeModel. The rest of the settings are the same as the previous quantitative simulation (time step=0.01, simulation time=10, integration mode: taylor method) apart from the simulation mode. The following simulation modes can be selected for the simulation: "Extreme Points Simulation", "Monte Carlo Point Simulation", and "Extreme Points & Monte Carlo Points Simulation", which combines both extreme point and Monte Carlo simulation. If "Monte Carlo Point Simulation" or "Extreme Points & Monte Carlo Points Simulation" is selected, the number of points used for the Monte Carlo simulation should be provided: the larger this number is, the slower and more precise the simulation becomes.

Semi-quantitative simulation II
To perform the semi-quantitive simulation as shown in Figures 8 and 9, select the initial value files Initial StateSemiQPe=0.558kHog=0.3-0.5.txt and Initial SemiQPe=0.45-0.56Khog0.3-0.5.txt, respectively. These two files can be found in the folder Data/OsmoticStressModel/ SemiQuantitativeModel. Other settings are the same as those used for the previous semiquantitative simulation.