BioNessie Tutorial

Simulating MAPK Pathway Models and Model Checking

Xuan Liu and Robin Donaldson

This tutorial will:

• Introduce you to simulating models with the BioNessie workbench.
• Allow you to explore and edit the model definition.
• Introduce deterministic MC2 model checker with output from BioNessie that you create.
• Show how stochastic MC2 model checker can be used with Gillespie simulation, through precomputed simulation output.

NOTE:

• The presentation slides and user manuals (BioNessie and MC2) will provide help with the following tasks. They detail how to use the BioNessie simulator and also contain run commands for MC2 in Unix shell.

• Software can be found in the following locations: BioNessie, and mc2.

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1. In BioNessie, simulate the RKIP model which you can find in BioNessie's default model folder yourBioProject/models/RKIPpathway.xml with 60 time units and 120 time steps.

(Cho, K.H., Shin, S.Y., Kim, H.W., Wolkenhauer, O., McFerran, B., Kolch, W.: "Mathematical modeling of the influence of RKIP on the ERK signaling pathway". Lecture Notes in Computer Science 2602 (2003) 127-141)

2. Perform a standard Parameter Scan of the RKIP model for k2 over the range of values between 0 and 5 with the settings below.

· Param Scan Option = k2

· Param Begin value = 0; Param End Value = 5

· Param Steps = 10

· Total time = 200; Time step = 200.

3. Perform a standard Parameter Scan of the Levchenko model levchenko.xml for Ras_GTP over the range of values between 0.1 and 1.0 with the settings below.

(Levchenko et al. "Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties". Proc Natl Acad Sci USA, 97(11):5818-5823, 2000.)

· Param Scan Option = Ras_GTP

· Param Begin value = 0.1; Param End Value = 1.0

· Param Steps = 9

· Total time = 200; Time step = 200.

4. Perform a Model Fitting of the RKIP model with the settings below. The target curve/observed curve (raf1.txt) is provided in the CD.

· Arithmetic = GA

· Circle =64

· Results Count = 3

· Target Parameters Setting

o Target Parameter = k1; Begin value = 0.1; End Value = 1.0; Steps = 20

o Target Parameter = k2; Begin value = 0.1; End Value = 1.0; Steps = 20

5. Load the Levchenko model of the MAPK pathway into BioNessie and simulate for 300 time units with 300 time steps. Save the (non-XML) output of this simulation to a file in your filespace for use with the MC2 model checker.
   
   Run the model checker against this output with the C1, C2 and C3 properties queries/C.queries.

6. Load the Kholodenko model of the MAPK pathway into BioNessie and simulate for 5,000 time units with 100 time steps. Again, save the output to file and perform MC2 model checking of this output using the oscillation queries queries/oscillation.queries.
   
   (Kholodenko (2000), "Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades". Eur. J. Biochem. 2000, 267(6): 1583-1588.)
   Notice that the queries check for varying numbers of oscillations. Can you check for more oscillations in a longer time period?

7. Perform stochastic model checking using MC2 we provide the Gillespie2 simulator. There may be issues when compiling the Gillespie2 simulator included, so to get you started we have provided precomputed simulation outputs from Gillespie2.
   
   Run the MC2 model checker against the simulation output of Levchenko with 4 molecules simulation_outputs/levchenko_4_output with the S1 query S1_4.queries and the S2 query S2_4.queries.