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RuleBender

RuleBender. A Tutorial. Outline. Rule- based Modeling BioNetGen Language (BNGL) RuleBender. Rule-based Modeling. Molecules Types Names Initial Concentrations Molecular Interactions Reactants and Products Reaction Directions Reaction Rates. Rule-based Modeling.

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RuleBender

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  1. RuleBender A Tutorial

  2. Outline • Rule-based Modeling • BioNetGen Language (BNGL) • RuleBender

  3. Rule-based Modeling • Molecules • Types • Names • Initial Concentrations • Molecular Interactions • Reactants and Products • Reaction Directions • Reaction Rates

  4. Rule-based Modeling Molecules – Data Objects: Ligand L Receptor R Adaptor A Kinase K Molecular Interactions - Rules: L can bind to R Two R can dimerize if they are bound to L A can bind R, regardless of whether it is bonded to L/dimerized or not A can bind K, regardless of its phosphorylation state K can be phosphorylated When bound to A, one K can transphosphorylatethe other … A Simple Model: Toy-Jim

  5. Rule-based Modeling A Simple Model: Toy-Jim http://www.biology.arizona.edu/cell_bio/problem_sets/signaling/02t.html

  6. Rule-based Modeling Rules: L + R <-> LR LR + LR <-> LRLR A + R <-> AR A + K <-> AK … Problems How to express a bond? How to express a molecule’s binding state? How to express phosphorylation state? Solution: BioNetGen Language A Simple Model: Toy-Jim

  7. BioNetGen Language BioNetGen Software Set

  8. BioNetGen Language A BNGL program consists of following blocks: Parameters Molecule Types Seed Species Reaction Rules Observables Actions Elements of a BNGL program

  9. BioNetGen Language MoleculeTypes • Surrounded by • begin molecule types • end molecule types • Declare a Molecule: • Molecule name • List of Components in Parentheses • Tilde character (‘~’) after the component to declare the state of the component • ALL possible components and states should be declared In toy-jim.bngl: begin molecule types 1 L(r) 2 R(l, r, a) 3 A(r, k) 4 K(a, Y~U~P) begin molecule types

  10. BioNetGen Language Seed Species • Molecules / Complexes and concentrations present at the initial time • Surround by • begin seed species • end seed species • Bindings to form a Complex • Use ‘.’ to concatenate two molecules • Use ‘!’ followed by a bond name (Integer) to declare the binding position • Each bond name must occur TWO times within a species. begin seed species L(r) 0 R(l, r, a) R0 A(r, k) A0 K(a, Y~U) K0 end seed species

  11. BioNetGen Language Seed Species • Example • Ligand and Receptor binding • L(r!1).R(l!1,r) • = L(r!2).R(l!2,r)

  12. BioNetGen Language Seed Species • Exercise: • What is the structure of Complex: L(r!1).R(l!1,r!3).L(r!2).R(l!2,r!3) • How many bounds are there? • Can you draw it?

  13. BioNetGen Language Reaction Rules • Surrounded by • begin reaction rules • end reaction rules • Molecules - Pattern Matching Molecules / Complexes do NOT have to be fully specified • Components of defined molecules may be missing • K(Y~P) matches K(a,Y~P) • State labels may be absent • K(a, Y) matches K(a, Y~U) and K(a, Y~P) • Edge names may be given with wildcards to select various connectivity • “?”: a bond may or may not be present • “+”: a bond must be present • Other molecules in a complex may be absent • R(r!+) matches all dimerized R

  14. BioNetGen Language Exercise: Which of the following does pattern A(r!+,k!?) match? 1. A(r!1).R(a!1) 2. A(r,k!2).K(a!2, Y~P) 3. R(a!1).A(r!1,k!2).K(a!2) 4. A(r!+,k!+) 5. A(r!?,k!?) 6. L(r!8).R(l!8,a!4,r!7).A(r!4).R(r!7,l!11).L(r!11) 7. A.A Reaction Rules

  15. BioNetGen Language Reaction Rules • Declare a Reaction • Direction • One direction: -> • Both directions: <-> • Reactants: Left hand side • Products: Right hand side • Reaction rates

  16. BioNetGen Language begin reaction rules # Ligand Receptor Binding L(r) + R(l,r) <-> L(r!1).R(l!1,r) kpL, kmL # Receptors can dermize if bounded to Ligand L(r!1).R(l!1,r) + L(r!1).R(l!1,r) <-> L(r!1).R(l!1,r!3).L(r!2).R(l!2,r!3) kpD,kmD # Adaptor and Receptor binding A(r) + R(a) <-> A(r!1).R(a!1) kpA,kmA # Adaptor and Kinase binding, regardless of phosphorylation state A(k) + K(a) <-> A(k!1).K(a!1) kpK,kmK Reaction Rules

  17. BioNetGen Language # Kinase transphosphorylation K(Y~U).K(Y~U) -> K(Y~U).K(Y~P) pK # Kinase transphosphorylation K(Y~P).K(Y~U) -> K(Y~P).K(Y~P) pKs # Dephosphylation in membrane complex R(a!1).A(r!1,k!2).K(a!2,Y~P) -> R(a!1).A(r!1,k!2).K(a!2,Y~U) dM # Dephosphylation in cytosol K(a,Y~P) -> K(a,Y~U) dC end reaction rules Reaction Rules

  18. BioNetGen Language Reaction Rules

  19. BioNetGen Language Exercise What is the reaction describing An Adapter with a bond to a dermized Receptor Binds A Kinase One direction, reaction rate kp R(r!+,a!1).A(r!1,k)+K(a) -> R(r!+,a!1).A(r!1,k!2).K(a!2) kp Reaction Rules

  20. BioNetGen Language Parameters • Surrounded by • begin parameters • end parameters • Defines parameters in • Initial concentrations • Reaction Rates begin parameters # initial concentrations L0 1 R0 1 … # reaction rates kpL 0.1 kmL 0.1 … end parameters

  21. BioNetGen Language Observables • Surrounded by • begin observables • end observables • Type: • Species • Fully defined molecules/ Complexies • Molecules • Weighted sum over Species matched by the pattern • Name • Pattern begin parameters Molecules RecDimR(r!+) MoleculesRec_A R(a!1).A(r!1) … Molecules L_tot L … end parameters

  22. BioNetGen Language Actions • Generate Network • generate_network • Simulation with an ODE solver • simulate_ode • Simulation with Stochastic Simulation Algorithm • simulate_ssa • Set up a simulation • simulate_xxx({param1=>val1,param2=>val2,…}) • Simulation Parameters: • t_end • Simulation end time • n_steps • Number of intervals at which to report concentrations • atol, rtol • Absolute error tolerance • Relative error tolerance • sample_times • Times at which to report concentrations • suffix/prefix • The suffix/prefix of the result file

  23. RuleBender The Graphical Interface of BNGL

  24. RuleBender Basic Operations • Create a new file • Load a saved file • Save

  25. RuleBender Visualizing a Model • Contact Map • Connections between Molecules • Click a Component can get its States information • Click a Bond between two molecules can get the associated Reaction information (Reactants, Products, Reaction Rates)

  26. RuleBender Visualizing a Model • Influence Graph • Influences between two reactions • Reactions with one direction • Reactions with two directions

  27. RuleBender Simulation & Result Analysis • Click ‘Run’ • Simulation information showed in ‘Console’ • Generate: • CDAT: concentrations of all molecules • GDAT: concentrations of all observables • Result Viewer • Concentrations of Observables over the simulation time period

  28. RuleBender Parameter Scan • Run several simulations changing ONE parameter

  29. RuleBender Parameter Scan • Report how the changing of the parameter affects the other reactions • Plot a graph • Initial Value of the selected parameter vs. Concentrations of Observables

  30. The END Thank You!

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