Rule-based modeling for protein-protein interaction networks-the Cyanobacterial circadian clock as a case study

Rule-based modeling is a new approach to cope with the inherent combinatorial complexity in protein-protein interaction networks, such as cellular signaling pathways. In contrast to reactions that act on chemical species, rules can act on partially specified species. A single rule can thus account for multiple reactions and reflects the limited local context on which most protein-protein interaction events are conditioned on. The cyanobacterial circadian clock is purely protein-based and is centered around the cyclic phosphorylation of the hexameric KaiC protein. Its different phosphorylation states give rise to a combinatorial number of species that would be required for a traditional description. We give a detailed rule-based model, incorporating recent experimental findings of twosite phosphorylation and monomer exchange of the KaiC hexamer. Monte-Carlo sampling of kinetic parameters shows that monomer exchange alone may not be sufficient to synchronize the KaiC hexamers.