CONICET | Buscador de Institutos y Recursos Humanos

The nonlinearities found in molecular networks usually prevent mathematical analysis of networkbehaviour, which has largely been studied by numerical simulation. This can lead to difficult problems of parameter determination. However, molecular networks give rise, through mass-action kinetics, to polynomial dynamical systems, whose steady states are zeros of a set of polynomial equations. These equations may be analysed by algebraic methods, in which parameters are treated as symbolic expressions whose numerical values do not have to be known in advance. For instance, an invariant of a network is a polynomial expression on selected state variables that vanishes in any steady state. Invariants have been found that encode key network properties and that discriminate between different network structures. Although invariants may be calculated by computational algebraic methods, such as Gr¨obner bases, these become computationally infeasible for biologically realistic networks. Here, we exploit Chemical Reaction Network Theory (CRNT) to develop an efficient procedure for calculating invariants that are linear combinations of complexes, or the monomials coming from mass action. We show how this procedure can be used in proving earlier results of Horn and Jackson and of Shinar and Feinberg for networks of deficiency at most one. We then apply our method to enzyme bifunctionality, including the bacterial EnvZ/OmpR osmolarity regulator and the mammalian 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase glycolytic regulator, whose networks have deficiencies up to four. We show that bifunctionality leads to different forms of concentration control that are robust to changes in initial conditions or total amounts. Finally, we outline a systematic procedure for using complex-linear invariants to analyse molecular networks of any deficiency.