Exact Hybrid Particle/Population Simulation of Rule-Based Models of Biochemical Systems

Detailed modeling and simulation of biochemical systems is complicated by the problem of combinatorial complexity, an explosion in the number of species and reactions due to myriad protein-protein interactions and post-translational modifications. Rule-based modeling overcomes this problem by representing molecules as structured objects and encoding their interactions as pattern-based rules. This greatly simplifies the process of model specification, avoiding the tedious and error prone task of manually enumerating all species and reactions that can potentially exist in a system. From a simulation perspective, rule-based models can be expanded algorithmically into fully-enumerated reaction networks and simulated using a variety of network-based simulation methods, such as ordinary differential equations or Gillespie's algorithm, provided that the network is not exceedingly large. Alternatively, rule-based models can be simulated directly using particle-based kinetic Monte Carlo methods. This “network-free” approach produces exact stochastic trajectories with a computational cost that is independent of network size. However, memory and run time costs increase with the number of particles, limiting the size of system that can be feasibly simulated. Here, we present a hybrid particle/population simulation method that combines the best attributes of both the network-based and network-free approaches. The method takes as input a rule-based model and a user-specified subset of species to treat as population variables rather than as particles. The model is then transformed by a process of “partial network expansion” into a dynamically equivalent form that can be simulated using a population-adapted network-free simulator. The transformation method has been implemented within the open-source rule-based modeling platform BioNetGen, and resulting hybrid models can be simulated using the particle-based simulator NFsim. Performance tests show that significant memory savings can be achieved using the new approach and a monetary cost analysis provides a practical measure of its utility.Author Summary: Rule-based modeling is a modeling paradigm that addresses the problem of combinatorial complexity in biochemical systems. The key idea is to specify only those components of a biological macromolecule that are directly involved in a biochemical transformation. Until recently, this “pattern-based” approach greatly simplified the process of model building but did nothing to improve the performance of model simulation. This changed with the introduction of “network-free” simulation methods, which operate directly on the compressed rule set of a rule-based model rather than on a fully-enumerated set of reactions and species. However, these methods represent every molecule in a system as a particle, limiting their use to systems containing less than a few million molecules. Here, we describe an extension to the network-free approach that treats rare, complex species as particles and plentiful, simple species as population variables, while retaining the exact dynamics of the model system. By making more efficient use of computational resources for species that do not require the level of detail of a particle representation, this hybrid particle/population approach can simulate systems much larger than is possible using network-free methods and is an important step towards realizing the practical simulation of detailed, mechanistic models of whole cells.