Systematic model reduction captures the dynamics of extrinsic noise in biochemical subnetworks

We consider the general problem of describing the dynamics of subnetworks of larger biochemical reaction networks, e.g., protein interaction networks involving complex formation and dissociation reactions. We propose the use of model reduction strategies to understand the "extrinsic" sources of stochasticity arising from the rest of the network. Our approaches are based on subnetwork dynamical equations derived by projection methods and path integrals. The results provide a principled derivation of different components of the extrinsic noise that is observed experimentally in cellular biochemical reactions, over and above the intrinsic noise from the stochasticity of biochemical events in the subnetwork. We explore several intermediate approximations to assess systematically the relative importance of different extrinsic noise components, including initial transients, long-time plateaus, temporal correlations, multiplicative noise terms, and nonlinear noise propagation. The best approximations achieve excellent accuracy in quantitative tests on a simple protein network and on the epidermal growth factor receptor signaling network.