Response to temporal parameter fluctuations in biochemical networks.

Metabolic response coefficients describe how variables in metabolic systems, like steady state concentrations, respond to small changes of kinetic parameters. To extend this concept to temporal parameter fluctuations, we define spectral response coefficients that relate Fourier components of concentrations and fluxes to Fourier components of the underlying parameters. It is also straightforward to generalize other concepts from metabolic control theory, such as control coefficients with their summation and connectivity theorems. The first-order response coefficients describe forced oscillations caused by small harmonic oscillations of single parameters: they depend on the driving frequency and comprise the phases and amplitudes of the concentrations and fluxes. Close to a Hopf bifurcation, resonance can occur: as an example, we study the spectral densities of concentration fluctuations arising from the stochastic nature of chemical reactions. Second-order response coefficients describe how perturbations of different frequencies interact by mode coupling, yielding higher harmonics in the metabolic response. The temporal response to small parameter fluctuations can be computed by Fourier synthesis. For a model of glycolysis, this approximation remains fairly accurate even for large relative fluctuations of the parameters.