BioNessie is an integrated software platform for the composition, simulation and analysis of biochemical networks which is being developed by the Systems Biology team at the Bioinformatics Research Centre as a part of a large DTI funded project BPS: A Software Tool for the Simulation and Analysis of Biochemical Networks. It simulates the kinetics of models of biochemical networks and provides users with functions of parameter scans and sensitivity analysis. BioNessie is currently being integrated with a number of web services which will allow advanced analysis to be performed on a computational cluster or GRID.
This document is a step-by-step guide to use features of BioNessie to construct, simulate and analyse models of biochemical networks. The first two sections of this document are focused on SBML model construction and simulation. The last section illustrates the use of parameter scans and sensitivity analysis.There are two ways of contructing models in BioNessie, creating a model from scratch and creating a model based on an existing model. For the later, refer to the section of how to upload a model in BioNessie. To construct a model from scratch, following steps are essential and must be carried out in the order as it is introduced below:
Step1: Model Settings
Models, paramscan (Parameter Scans), sens (Sensitivity Analysis) and Simulations. On the top, you can see a menu bar, followed by a few of functional icons located below. The command Kineti Law Creator at the far end of the icon bar is used to create user-defined kinetic laws, which will be explained later.
File->New Project, which brings out a dialog. Clicking Next leads you to the page where you can assign the name and define the path for this new project. Click Finish to terminate the project settings. You can see that your project has been added to the tree on the left side of the window.
models and follow New->File/Folder, which will lead you to a dialog. Choose the name of the project for which you are going to create a SBML model. Select the Others from the list box on the left side of the page and SBML Template from the list box on the right side, and click Next. Give a more expressive name to the model, select the folder where you are going to save the SBML model and click Next. Accept the defaults of the last page and click Finish to complete the model settings. You can see that a panel with five main elements is displayed on the right side of the window, and they are Species, Parameters, UnitDefinitions, Reactions and Compartments. Following steps will explain what these elements are used for.
Models. You will see that your SBML model is right there.
Step 2: Compartment Definition
Compartments tag on the top of the panel. Click the button New Compartment in bottom right corner, and give a name to the new compartment in the dialog popped up (normally, we will give the name as compartment1, compartment 2, etc.). Click OK to exit the dialog.
Add to save the compartment just created. You can also edit or delete an existent compartment by clicking Delete or Change Commit button.
size, spatial dimension and volume of the compartment the BioNessie will use in the model. You will need to assign values to those parameters.
NOTE: You can create several SBML models and a few of different compartments for your project, but you have to put everything of each model into the same compartment.
Step3: Species Definition
Species tag on the top of the panel. Click the button New Species in bottom right corner. Enter a name to the new species in the dialog popped up, and click OK to exit.
Add to save the species just added. You can also delete or edit an existent species by clicking Delete or Change Commit button.
Owner compartment and allocate it to species.
Step4: Parameter Definition
Parameters tag (right next to the tag Species). Click the button New Parameter in bottom right corner. Give a name to this newly defined parameter in the dialog popped up, and click OK to exit.
Add to save the parameter just added. You can also delete or edit an existent parameter by clicking Delete or Change Commit button.
Step5: Reaction Input
Reaction tag (on the left side of the button Compartments). Click the button Add new Reaction. This will bring out a new dialog, where you can define a chemical reaction that will be included in the SBML model. Give an expressive name to the reaction and type it in the Reaction text box. You will see that BioNessie classifies all species involved in the reaction into reactants and products automatically.
Edit, which will lead you to a new dialog titled "Edit Reaction's formula". To assign a predefined kinetic law, select a kinetic law from the box at the top and click Refresh to validate the selection. Click commit to save this assignment and exit the dialog. Click OK to complete the Reaction Input.
How to create a user-defined kinetic type?
You can also assign a user-defined kinetic law to a reaction. To do this, go through the following steps:
Kinetic Law Creator. Give a name and write a formula of the kinetic law in the text box. The formula will be composed of species linked with mathematical operators (+, -, *, /).
Reversible Reaction if the reaction for which you are going to assign the user-defined kinetic law is reversible, otherwise check the box Inreversible Reaction.
To upload an existing model with BioNessie, follow File->Open File from the main menu and select the folder where the model is included. You will need to activate the file uploaded first before performing any operations. To do this, go the upper right corner of the panel and click the button Save to save the model under the BioNessie project that you are working with. You can see that the model has already added to the tree at the left side of the window.
To simulate a SBML model, go to the tree, right click on the SBML model under the Models folder and select Simulate. This will lead you to the simulation panel. Go to bottom left corner of the panel, define the total time (the starting time point is set as 0 by default; the total time represents the ending point of a time interval over which a simulation will be performed) and steps (the number of time points sampled over the interval) that BioNessie will use for the simulation. You can change step size and total time to observe how the curves look: curves will be getting smoother with an increase in the number of steps, but in the cost of more computational time. You can get the simulation results by double-clicking on the folder simulation in the tree file. There are two ways of generating simulation results: you can either run a simulation first and then save its results later, or run a simulation meanwhile having the results saved which can be achieved by clicking button Save Results before running a simulation (by clicking on Simulate).
In BioNessie, 60 and 120 are used as default values of the total time and time steps for a simulation, but you can also change these values to see how the curves respond. For example, the curves will be getting much smoother with an increase in the number of steps, but in the cost of more computational time. You can also have a particular part of the graph zoomed in or zoomed out, which can be achieved by pressing and holding down the left button on the mouse and draging open a box around the place where you want to zoom in. To zoom out, click the right mouse botton and follow Zoom Out->Both Axes. To go back to the original graph, click the right mouse button and follow Auto Range->Both Axes.
To set up a scan, go to the tree, right click on the SBML model and select Create Parameter Scan. This will lead you to a dialog. Give a more expressive name to the scanning task and specify associated attributes, which include selecting a parameter to be scanned, defining the minimum (Begin Value) and maximum (End Value) of an interval over which the parameter will be scanned, and dividing the interval into subintervals (Steps) to get specific parameter values. BioNessie will run simulations for each value over the interval. You will also need to specify the total time and time steps for the simulation. Click OK to finish the scan settings. Now, you can see a panel at the right side of the window with all information about the scan you just designed.
How to perfrom a standard parameter scan?
To run a standard parameter scan, go to the bottom right corner and click on the buttonDo Local Parameter Scan Now!. You can see how much the task has been processed from the progress bar. It normally takes a few second, which of course depends on the density and quantity of parameter values. After the computation is done, go to the top of the panel and click on the button Multi-Sims, which leads you to a page with a graphical viewer at the left side and the parameter values at the right side. Select a species from the selected box above the viewer to observe its dynamic behaviour (time-dependent) in response to each specific value of the parameter. You can also focus on investigating the effect of a paticular parameter value on dynamics of the species by dismissing the boxes of other parameter values.
How to perform a monitoring-function based parameter scan?
To run a monitoring-function based parameter scan, go to the top of the panel and click on the tagMonitor Formulas to define a monitoring function which the BioNessie will apply to compute scanning results. You need to give an expressive name to the function and write the formula (which will be in the form of a mathematical expression where players of the formula are connected with mathematical operations). Click Add to save the function, and now you are ready to scan the parameter. Go the bottom right corner and click on the button Do Local Parameter Scan Now!. You can see how much the task has been processed from the progress bar. It normally takes a few second, which of course depends on the density and quantity of parameter values. After the computation is done, go to the top of the panel and click the tag Chart Results to view the results. You can see a graphical viewer on the left side of the window and a list with three options on the right side. The three options, Max, Min and Final, represents the maximum, minimum and final value of a monitoring function in each simulation with a specific value of the parameter over the time interval. Choose a monitor function from the box above the viewer to explore the relationship between the function and the parameter. For each parameter, scanning results will be different with the monitoring function selected. You can also focus on one of the three options by dismissing other two boxes.
To create a sensitivity analysis, go to the tree, right click on the SBML model and select Create Sensitivity. This will lead you to a dialog where you can create a task of sensitivity analysis. Give an expressive name and define following parameters, which include selecting a parameter to be analysed, giving total time and time steps that the BioNessie will use for computing the results. Click OK to complete the settings. Now, you can see a panel with information about the task of the sensitivity analysis you just designed on the right side of the window. Go to the bottom right corner of the panel and click Do Sensitivity Analysis. You can view the results by clicking the tag Chart on the top of the panel.