Bioinformatics - Lab 9
Biochemical Pathways
David Gilbert and Xu Gu

The purpose of this lab is to give you practical experience in the construction and simulation of models of biochemical networks.

This lab refers to the slides for the lecture on Modelling dynamic behaviour.

Software

Matlab:

• Matlab is a modelling and simulation language that encourages the experimentation of system biology models. In Matlab, models of biochemical pathways are written as functions (M files), which are then solved with differential equations solvers (e.g. ode15 and ode45).
• Matlab can be run at any local machine.

BioNessie:

• BioNessie http://www.bionessie.com is a software tool which allows users to compose models of biochemical systems using biochemical equations, and to save these models as in SBML format (see http://www.sbml.org for model details on SBML---basically, it is a mark-up language for biochemical models).
• BioNessie enables the simulation of dynamic behaviour of biochemical models using a differential equation solver, and displays the results graphically. It also supports advanced analysis methods, including parameter scans and sensitivity analysis.
• BioNessie is available at /local/brccontrib/bin/bpi. For more information about using BioNessie, please see the user manual.

Exercises 1

Descriptions

Rate constants and initial concentrations required for the simulation are:

1. Rate Constants: k1 = 1; k2 = 0.5; k3 = 2
2. Initial Concentrations: [A] = 5; [B] = 1; [C] = 0; [D] = 0; [E] = 1; [AE]= 0;

See slides variable from the lecture notes for the Matlab code of equation (1) and equation (2) respectively. Click here to see how to create models in Matlab.

Exercise 2

(A) With the experience of modelling equation(5), can you code and simulate (i) a Metabolic Pathway and (ii) Signalling Pathway in BioNessie? See slides variable from the lecture notes for more details of the pathways. Refer to the following information to model and simulate the pathways.

1. Rate constants are the same as that in equation (5).
2. Initial concentrations of all enzyme-substrate complexes are given to 0.
3. Initial concentrations of substrates, products and enzymes involved in these two pathways are:
   • Metabolic Pathway: [E1] = [E2] = [E3] = 1; [S] = 100; [S'] = [S''] = [S'''] = 0
   • Signalling Pathway: [Input Signal] = 1; [S1] = [S2] = [S3] = 100; [P1] = [P2] = [P3] = 0

(B) Model and simulate the above pathways in Matlab. Can you tell the difference in the usability of command-line based simulator and equation-based simulator?

Exercise 3

Use BioNessie to perform a simulation and advanced analysis of the model of Raf-1/RKIP/ERK pathway. Click here to view the topology of the pathway. An available SBML model of the pathway can be downloaded here (right click on the link and save it with the name RKIP.xml).

(A) Run a time-plot simulation of the model (RKIP.xml) in BioNessie. Refer to the user manual for uploading SBML files with BioNessie.

(B) Perform parameter scans and sensitivity analysis of the SBML model (RKIP.xml). Parameter scans and sensitivity analysis are two commonly used approaches for understanding the dynamics of a biochemical model. Basically, parameter scanning is to explore a model's behaviour over different ranges of parameter values, which is achieved by running simulations for specific values in the range. Sensitivity analysis is to study the response of system variables to changes in parameter values, which can be used to identify key reactions and species as well as monitoring the robustness of a model.

1. Perform a standard parameter scan for k2 over the range of values between 0 and 5 with the settings below. Go to the user manual for running a parameter scan in BioNessie.
   • Param Scan Option = k2
   • Param Begin value = 0; Param End Value = 5
   • Param Steps = 10
   • Total time = 200; Time step = 200
2. Perform a monitoring-function based parameter scan for k2 with the same settings as defined above. In addition to view changes in dynamics of each individual species over a range of parameter values, you can also examine the response of some particular targets by defining corresponding monitoring functions. Go to the user manual for running a monitoring-function based parameter scan.
   In this exercise, you will use BioNessie to run two monitoring-function based parameter scans:

   • Monitoring function: ERK + RKIP. The function examines the effect of k2 on the total concentration of ERK and RKIP.
   • Monitoring function: MEKPP * RP. The function examines the effect of k2 on the production of the concentrations of MEKPP and RP.
3. Perform a sensitivity analysis for the parameter k6 with the following settings. Go to the user manual for running a sensitivity analysis in BioNessie.
   • Total time = 200; Time steps = 200