Homework: Rule-based modeling

Develop a rule-based model for a system of the sort described below and use BioNetGen to analyze the model.

Consider a dimer of receptor tyrosine kinases (RTKs). You may consider the receptors in a dimer to be either tightly associated (for simplicity) or loosely associated through a ligand-induced receptor-receptor interaction. See this sketch for a picture of what I have in mind. Each RTK contains a protein tyrosine kinase (PTK), of course, and n sites of autophosphorylation. Autophosphorylation is through a trans mechanism, i.e., a PTK can catalyze the phosphorylation of peptide substrates in a neighboring receptor but (for steric reasons) not within its own receptor. Phosphorylation is reversed by phosphatases available in excess through a pseudo first-order process (for simplicity) or you can explicitly include a membrane or cytosolic phosphatase in your model. Consider different values of n. An adapter protein or set of adapter proteins interacts with the receptor via SH2 domain or PTB domain recognition of phosphotyrosine(s). Consider competition and scenarios with and without cooperativity. Can you find a small system of ODEs that describes one of these scenarios? The PTK is a Michaelis-Menten enzyme. In other words, the following reaction scheme applies: E + S <-> (ES) -> E + P. Note that enzyme and substrate(s) are co-localized in a very small volume within a receptor-containing complex. Consider cases where [S]>>K_M (the enzyme is saturated) and [S]<<K_M (substrate is limiting), where K_M is the usual Michaelis-Menten constant and [S] is (local) substrate concentration. What is different about these two cases? How many distinct species can be potentially populated according to your model? Can you find parameter values for which phosphorylation of a set of receptor tyrosines occurs in an ordered sequence? For more guidance, see the extended write up of this homework problem.

Back to The Second q-bio School.