Cycles are abundant in most kinds of networks, especially in biological ones. Here, we investigate their role in the evolution of a chemical reaction system from one self-sustaining composition of molecular species to another and their influence on the stability of these compositions. While it is accepted that, from a topological standpoint, they enhance network robustness, the consequence of cycles to the dynamics are not well understood. In a former study, we developed a necessary criterion for the existence of a fixed point, which is purely based on topological properties of the network. The structures of interest we identified were a generalization of closed autocatalytic sets, called chemical organizations. Here, we show that the existence of these chemical organizations and therefore steady states is linked to the existence of cycles. Importantly, we provide a criterion for a qualitative transition, namely a transition from one self-sustaining set of molecular species to another via the introduction of a cycle. Because results purely based on topology do not yield sufficient conditions for dynamic properties, e.g. stability, other tools must be employed, such as analysis via ordinary differential equations. Hence, we study a special case, namely a particular type of reflexive autocatalytic network. Applications for this can be found in nature, and we give a detailed account of the mitotic spindle assembly and spindle position checkpoints. From our analysis, we conclude that the positive feedback provided by these networks' cycles ensures the existence of a stable positive fixed point. Additionally, we use a genome-scale network model of the Escherichia coli sugar metabolism to illustrate our findings. In summary, our results suggest that the qualitative evolution of chemical systems requires the addition and elimination of cycles.

A common problem in the analysis of biological systems is the combinatorial explosion that emerges from the complexity of multi-protein assemblies. Conventional formalisms, like differential equations, Boolean networks and Bayesian networks, are unsuitable for dealing with the combinatorial explosion, because they are designed for a restricted state space with fixed dimensionality. To overcome this problem, the rule-based modeling language, BioNetGen, and the spatial extension, SRSim, have been developed. Here, we describe how to apply rule-based modeling to integrate experimental data from different sources into a single spatial simulation model and how to analyze the output of that model. The starting point for this approach can be a combination of molecular interaction data, reaction network data, proximities, binding and diffusion kinetics and molecular geometries at different levels of detail. We describe the technique and then use it to construct a model of the human mitotic inner and outer kinetochore, including the spindle assembly checkpoint signaling pathway. This allows us to demonstrate the utility of the procedure, show how a novel perspective for understanding such complex systems becomes accessible and elaborate on challenges that arise in the formulation, simulation and analysis of spatial rule-based models.

This work provides a mathematical technique for analyzing and comparing infection dynamics models with respect to their potential long-term behavior, resulting in a hierarchy integrating all models. We apply our technique to coupled ordinary and partial differential equation models of SARS-CoV-2 infection dynamics operating on different scales, that is, within a single organism and between several hosts. The structure of a model is assessed by the theory of chemical organizations, not requiring quantitative kinetic information. We present the Hasse diagrams of organizations for the twelve virus models analyzed within this study. For comparing models, each organization is characterized by the types of species it contains. For this, each species is mapped to one out of four types, representing uninfected, infected, immune system, and bacterial species, respectively. Subsequently, we can integrate these results with those of our former work on Influenza-A virus resulting in a single joint hierarchy of 24 models. It appears that the SARS-CoV-2 models are simpler with respect to their long term behavior and thus display a simpler hierarchy with little dependencies compared to the Influenza-A models. Our results can support further development towards more complex SARS-CoV-2 models targeting the higher levels of the hierarchy.

Unconventional computing devices operating on nonlinear chemical media offer an interesting alternative to standard, semiconductor-based computers. In this work we study in-silico a chemical medium composed of communicating droplets that functions as a database classifier. The droplet network can be “programmed” by an externally provided illumination pattern. The complex relationship between the illumination pattern and the droplet behavior makes manual programming hard. We introduce an evolutionary algorithm that automatically finds the optimal illumination pattern for a given classification problem. Notably, our approach does not require us to prespecify the signals that represent the output classes of the classification problem, which is achieved by using a fitness function that measures the mutual information between chemical oscillation patterns and desired output classes. We illustrate the feasibility of our approach in computer simulations by evolving droplet classifiers for three machine learning datasets. We demonstrate that the same medium composed of 25 droplets located on a square lattice can be successfully used for different classification tasks by applying different illumination patterns as its externally supplied program.