Site-graph rewriting languages, such as Kappa or BNGL, offer parsimonious ways to describe highly combinatorial systems of mechanistic interactions among proteins. These systems may be then simulated efficiently. Yet, the modeling mechanisms that involve counting (a number of phosphorylated sites for instance) require an exponential number of rules in Kappa. In BNGL, updating the set of the potential applications of rules in the current state of the system comes down to the sub-graph isomorphism problem (which is NP-complete). In this paper, we extend Kappa to deal both parsimoniously and efficiently with counters. We propose a single push-out semantics for Kappa with counters. We show how to compile Kappa with counters into Kappa without counters (without requiring an exponential number of rules). We design a static analysis, based on affine relationships, to identify the meaning of counters and bound their ranges accordingly.

Motivation: We present an overview of the Kappa platform, an integrated suite of analysis and visualization techniques for building and interactively exploring rule-based models. The main components of the platform are the Kappa Simulator, the Kappa Static Analyzer and the Kappa Story Extractor. In addition to these components, we describe the Kappa User Interface, which includes a range of interactive visualization tools for rule-based models needed to make sense of the complexity of biological systems. We argue that, in this approach, modeling is akin to programming and can likewise benefit from an integrated development environment. Our platform is a step in this direction. Results: We discuss details about the computation and rendering of static, dynamic, and causal views of a model, which include the contact map (CM), snaphots at different resolutions, the dynamic influence network (DIN) and causal compression. We provide use cases illustrating how these concepts generate insight. Specifically, we show how the CM and snapshots provide information about systems capable of polymerization, such as Wnt signaling. A well-understood model of the KaiABC oscillator, translated into Kappa from the literature, is deployed to demonstrate the DIN and its use in understanding systems dynamics. Finally, we discuss how pathways might be discovered or recovered from a rule-based model by means of causal compression, as exemplified for early events in EGF signaling. Availability and implementation: The Kappa platform is available via the project website at kappalanguage.org. All components of the platform are open source and freely available through the authors' code repositories.

We introduce the Dynamic Influence Network (DIN), a novel visual analytics technique for representing and analyzing rule-based models of protein-protein interaction networks. Rule-based modeling has proved instrumental in developing biological models that are concise, comprehensible, easily extensible, and that mitigate the combinatorial complexity of multi-state and multi-component biological molecules. Our technique visualizes the dynamics of these rules as they evolve over time. Using the data produced by KaSim, an open source stochastic simulator of rule-based models written in the Kappa language, DINs provide a node-link diagram that represents the influence that each rule has on the other rules. That is, rather than representing individual biological components or types, we instead represent the rules about them (as nodes) and the current influence of these rules (as links). Using our interactive DIN-Viz software tool, researchers are able to query this dynamic network to find meaningful patterns about biological processes, and to identify salient aspects of complex rule-based models. To evaluate the effectiveness of our approach, we investigate a simulation of a circadian clock model that illustrates the oscillatory behavior of the KaiC protein phosphorylation cycle.