Rule-Based Modelling and Model Perturbation

Rule-based modelling has already proved to be successful for taming the combinatorial complexity typical of cellular signalling networks. caused by the combination of physical protein-protein interactions and modifications that generate astronomical numbers of distinct molecular species However, traditional rule-based approaches, based on an unstructured space of agents and rules, remain susceptible to other combinatorial explosions caused by imitated and/or splice variant agents. that share most but not all of their rules with their wild-type counter parts and by drugs, which must: be clearly distinguished from physiological ligands In this paper, we define a syntactic extension of Kappa, an established rule-based modelling platform, that enables the expression of a structured space of agents and rules that allows us to express mutated agents, splice variants, families of related proteins and ligand/drug interventions uniformly. This also enables a anode of model construction where, starting from the current consensus model, we attempt to reproduce in numero the mutational and more generally the ligand/drug perturbational analyses that were used in the process of inferring those pathways in the first place.