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Rule-based Modelling and Model Perturbation Vincent Danos1, J′er?omeFeret2, Walter Fontana3, Russ Harmer4, and Jean Krivine3,5 1 University of Edinburgh 2 INRIA–ENS–CNRS 3 Harvard Medical School 4 CNRS–Universit′eParis Diderot 5 IHES Abstract. Rule-based modelling has already proved to be successful for taming the com- binatorial complexity, typical of cellular signalling networks, caused by the combination of physical protein-protein interactions and modi?cations that generate astronomical numbers of distinct molecular species. However, traditional rule-based approaches, based on an un- structured space of agents and rules, remain susceptible to other combinatorial explosions caused by mutated and/or splice variant agents, that share most but not all of their rules with their wild-type counterparts; and by drugs, which must be clearly distinguished from physiological ligands. In this paper, we de?ne 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 mode 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 ?rst place. 1 Introduction In recent years, there has been extensive development in the use of modelling to understand cellular signalling networks (see [1, ?,3, 4] among many others). To date, this line of work has focussed almost exclusively on de