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Modelling Biochemical Reactions - Tutorial Second Latin American School on Computational Neuroscience Kim “Avrama” Blackwell George Mason University Three Types of Objects • Pools of molecules – • Uni- and Bi-molecular Reactions – • Keep track of concentration Transformation of one or more molecules into equal number of another molecule Enzyme reactions – One enzyme molecule can transform multiple copies of substrate into equal number of product Compartment-Like Objects •Keep track of molecule quantities and concentrations • Similar to compartment calculating voltage –Requires geometry/morphology values • length • radius • area of outer surface • area of inner surface (can be zero) • area of side surface • volume Compartment-Like Objects • Keep track of molecule quantities and concentrations – rxnpool (Chemesis) • dC/dt = A - B C • A = change in quantity independent of present quantity • B = rate of change • Receives messages with quantities A and/or B from other objects (enzymes, reactions, also calcium influx) •RXN0 (A), RXN1 (B), RXN2 (A and B) Compartment-Like Objects • Keep track of molecule quantities and concentrations – – conservepool (Chemesis) • C = Ctot - Ci • Quantity is remainder after all other forms of molecule accounted for pool (Kinetikit) • dC/dt = A - B C • Or C = Ctot - Ci • Can also implement stochastic reactions (if flag is set to conserve) Concentration Pools • chemesis • genesis #1 > showobject rxnpool • genesis #2 > showobject conservepool • genesis #3 > showobject pool Enzyme and Reaction objects • Calculate changes due to reactions – mmenz (Chemesis) • Use if MM assumptions are met • Fields: Km and Vmax • Inputs: enzyme, substrate concentration • Calculates Vmax times [Enzyme] times [substrate] divided by ([substrate] + Km) • Send messages RXN0 or RXN0moles to rxnpool • Empirical feedback modification of enzyme activity can be added Enzyme and Reaction objects • Calculate changes due to reactions – – Enzyme (Chemesis) • Fields: Kcat, Kf, Kb • Inputs: enzyme, substrate quantity • Calculates amount of Enzyme-Substrate complex • Calculates change in product, enzyme, substrate Enz (kinetikit) • Fields: Kcat, Kf, Kb • Inputs: enzyme, substrate quantity • Can implement stochastic reactions Enzyme and Reaction objects • Calculate changes due to reactions – reaction (Chemesis) or reac (kinetikit) • Fields: kf, kb • Inputs (messages): substrates and products • Calculates: • – forward rate constant times substrate molecules – backward rate constant times product molecules send messages RXN0 - RXN2 to rxnpool Enzyme and Reaction objects • Genesis #4> showobject mmenz • Genesis #5> showobject enzyme – Compartment dimensions allows membrane bound enzyme to have different volume than substrate and products • Genesis #5> showobject enz • Genesis #6> showobject reaction • Genesis #7> showobject reac Creating Chemesis Simulation • Create rxnpool pool1 • Create conservepool pool2 • Setfield pool1 Cinit initvalue ... • Addmsg pool1 pool2 CONC Conc – mGlu-IP3-enz.g for complete examples Creating Chemesis Simulation • • • • • • Create reaction rxn1 Setfield rxn1 kf kfvalue kb kbvalue Addmsg pool1 rxn1 SUBSTRATE Conc Addmsg pool2 rxn1 SUBSTRATE Conc Addmsg pool3 rxn1 PRODUCT Conc Addmsg rxn1 pool1 RXN2 kbprod kfsubs – • To substrate – kbprod is first Addmsg rxn1 pool3 RXN2 kfsubs kbprod – To product – kfsubs is first Chemesis Example • Metabotropic receptor to PLC to IP3 – Include param.g – Include mGlu-IP3-enz.g Listglobals – – – Create neutral purkcell Create neutral glutamate (under purkcell) • Allow setting a concentration of neurotransmitter – Invoke function (no parentheses or commas) Include graphs.g (and invoke function) – Step (to run simulation) – XPP example • Xppaut mglu-ip3.ode – Evaluate role of aG decay – Evaluate role of IP3 decay