Stochastic Simulation of Biomolecular Networks in Dynamic Environments

Simulation of biomolecular networks is now indispensable for studying biological systems, from small reaction networks to large ensembles of cells. Here we present a novel approach for stochastic simulation of networks embedded in the dynamic environment of the cell and its surroundings. We thus sample trajectories of the stochastic process described by the chemical master equation with time-varying propensities. A comparative analysis shows that existing approaches can either fail dramatically, or else can impose impractical computational burdens due to numerical integration of reaction propensities, especially when cell ensembles are studied. Here we introduce the Extrande method which, given a simulated time course of dynamic network inputs, provides a conditionally exact and several orders-of-magnitude faster simulation solution. The new approach makes it feasible to demonstrate—using decision-making by a large population of quorum sensing bacteria—that robustness to fluctuations from upstream signaling places strong constraints on the design of networks determining cell fate. Our approach has the potential to significantly advance both understanding of molecular systems biology and design of synthetic circuits.Author Summary: Simulation algorithms have become indispensable tools in modern quantitative biology, providing deep insight into many biochemical systems, including gene regulatory networks. However, current stochastic simulation approaches handle the effects of fluctuating extracellular signals and upstream processes poorly, either failing to give qualitatively reliable predictions or being very inefficient computationally. Here we introduce the Extrande method, a novel approach for simulation of biomolecular networks embedded in the dynamic environment of the cell and its surroundings. The method is accurate and computationally efficient, and hence fills an important gap in the field of stochastic simulation. In particular, we employ it to study a bacterial decision-making network and demonstrate that robustness to fluctuations from upstream signaling places strong constraints on the design of networks determining cell fate.