Singularly Perturbed Monotone Systems and an Application to Double Phosphorylation Cycles

The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation ``futile cycle'' motif which plays a central role in eukaryotic cell signaling.Comment: 21 pages, 3 figures, corrected typos, references remove

Biological switches and clocks

To introduce this special issue on biological switches and clocks, we review the historical development of mathematical models of bistability and oscillations in chemical reaction networks. In the 1960s and 1970s, these models were limited to well-studied biochemical examples, such as glycolytic oscillations and cyclic AMP signalling. After the molecular genetics revolution of the 1980s, the field of molecular cell biology was thrown wide open to mathematical modellers. We review recent advances in modelling the gene–protein interaction networks that control circadian rhythms, cell cycle progression, signal processing and the design of synthetic gene networks

Type inference in systems biology

Abstract. Type checking and type inference are important concepts and methods of programming languages and software engineering. Type checking is a way to ensure some level of consistency, depending on the type system, in large programs and in complex assemblies of software components. Type inference provides powerful static analyses of preexisting programs without types, and facilitates the use of type systems by freeing the user from entering type information. In this paper, we investigate the application of these concepts to systems biology. More specifically, we consider the Systems Biology Markup Language SBML and the Biochemical Abstract Machine BIOCHAM with their repositories of models of biochemical systems. We study three type systems: one for checking or inferring the functions of proteins in a reaction model, one for checking or inferring the activation and inhibition effects of proteins in a reaction model, and another one for checking or inferring the topology of compartments or locations. We show that the framework of abstract interpretation elegantly applies to the formalization of these abstractions and to the implementation of linear time type checking as well as type inference algorithms. Through some examples, we show that the analysis of biochemical models by type inference provides accurate and useful information. Interestingly, such a mathematical formalization of the abstractions used in systems biology already provides some guidelines for the extensions of biochemical reaction rule languages.

A petri net approach to persistence analysis in chemical reaction networks

Summary. A positive dynamical system is said to be persistent if every solution that starts in the interior of the positive orthant does not approach the boundary of this orthant. For chemical reaction networks and other models in biology, persistence represents a non-extinction property: if every species is present at the start of the reaction, then no species will tend to be eliminated in the course of the reaction. This paper provides checkable necessary as well as sufficient conditions for persistence of chemical species in reaction networks, and the applicability of these conditions is illustrated on some examples of relatively high dimension which arise in molecular biology. More specific results are also provided for reactions endowed with mass-action kinetics. Overall, the results exploit concepts and tools from Petri net theory as well as ergodic and recurrence theory.

The total quasi-steady-state approximation for fully competitive enzyme reactions

none3The validity of the Michaelis-Menten-Briggs-Haldane approximation for single enzyme reactions has recently been improved by the formalism of the total quasi-steady-state approximation. This approach is here extended to fully competitive systems, and a criterion for its validity is provided. We show that it extends the Michaelis-Menten-Briggs-Haldane approximation for such systems for a wide range of parameters very convincingly, and investigate special cases. It is demonstrated that our method is at least roughly valid in the case of identical affinities. The results presented should be useful for numerical simulations of many in vivo reactions.noneM. PEDERSEN; BERSANI AM; BERSANI EPedersen, MORTEN GRAM; Bersani, Am; Bersani, E