RuleMonkey: software for stochastic simulation of rule-based models

Here, we present a software tool called RuleMonkey, which implements a network-free method for simulation of rule-based models that is similar to Gillespie's method. The method is suitable for rule-based models that can be encoded in BNGL, including models with rules that have global application conditions, such as rules for intramolecular association reactions. In addition, the method is rejection free, unlike other network-free methods that introduce null events, i.e., steps in the simulation procedure that do not change the state of the reaction system being simulated. We verify that RuleMonkey produces correct simulation results, and we compare its performance against DYNSTOC, another BNGL-compliant tool for network-free simulation of rule-based models. We also compare RuleMonkey against problem-specific codes implementing network-free simulation methods.RuleMonkey enables the simulation of rule-based models for which the underlying reaction networks are large. It is typically faster than DYNSTOC for benchmark problems that we have examined. RuleMonkey is freely available as a stand-alone application http://public.tgen.org/rulemonkey webcite. It is also available as a simulation engine within GetBonNie, a web-based environment for building, analyzing and sharing rule-based models.A great deal of knowledge about signal transduction, which is mediated largely by the interactions of proteins, has been built up over the years [1,2], in part because molecular changes that affect signal-transduction systems play a role in many diseases, such as cancer [3]. Signal-transduction systems are exceedingly complex, and as a result, our ability to manipulate the behaviors of these systems (e.g., through therapies based on molecularly targeted drugs [4]) is limited. To extend our understanding beyond that reachable through intuition alone, researchers are attempting to develop predictive mathematical models for signal-transduction systems [5-7]. These systems are difficult to