In the present work, we address a major challenge facing the modeling of biochemical reaction networks: when using stochastic simulations, the computational load and number of unknown parameters may dramatically increase with system size and complexity. A proposed solution to this challenge is the reduction of models by utilizing nonlinear reaction rate laws in place of a complex multi-reaction mechanism. This type of model reduction in stochastic systems often fails when applied outside of the context in which it was initially conceived. We hypothesize that the use of nonlinear rate laws fails because a single reaction is inherently Poisson distributed and cannot match higher order statistics. In this study we explore the use of Hill-type rate laws as an approximation for gene regulation, specifically transcription repression. We matched output data for several simple gene networks to determine Hill-type parameters. We show that the models exhibit inaccuracies when placed into a simple feedback repression model. By adding an additional abstract reaction to the models we account for second-order statistics. This split Hill rate law matches higher order statistics and demonstrates that the new model is able to more accurately describe the mean protein output. Finally, the modified Hill model is shown to be modular and models retain accuracy when placed into a larger multi-gene network. The work as presented may be used in gene regulatory or cell-signaling networks, where multiple binding events can be captured by Hill kinetics. The added benefit of the proposed split-Hill kinetics is the improved accuracy in modeling stochastic effects. We demonstrate these benefits with a few specific reaction network examples
Bibliographical noteFunding Information:
This work was supported by a grant from the National Institutes of Health (American Recovery and Reinvestment Act Grant No. GM086865) and a grant from the National Science Foundation (Grant No. CBET-0644792) with computational support from the Minnesota Supercomputing Institute (MSI).