A scalable method for parameter-free simulation and validation of mechanistic cellular signal transduction network models

The metabolic modelling community has established the gold standard for bottom-up systems biology with reconstruction, validation and simulation of mechanistic genome-scale models. Similar methods have not been established for signal transduction networks, where the representation of internal states leads to scalability issues in both model formulation and execution. While rule- and agent-based methods allow efficient model definition and execution, respectively, model parametrisation introduces an additional layer of uncertainty due to the sparsity of reliably measured parameters. Here, we present a scalable method for parameter-free simulation of mechanistic signal transduction networks. It is based on rxncon and uses a bipartite Boolean logic with separate update rules for reactions and states. Using two generic update rules, we enable translation of any rxncon model into a unique Boolean model, which can be used for network validation and simulation - allowing the prediction of system level function directly from molecular mechanistic data. Through scalable model definition and simulation, and the independence of quantitative parameters, it opens up for simulation and validation of mechanistic genome-scale models of signal transduction networks.