Stochastic Simulation of Biomolecular Networks in Dynamic Environments

This is the final version of the article. Available from Public Library of Science via the DOI in this record.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.MV acknowledges support under an MRC Biomedical Informatics Fellowship. PT acknowledges support by the Royal Commission for the Exhibition of 1851. RG acknowledges support from the Leverhulme Trust (RPG-2013-171). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript