The Theory of Matrices. By F R. Gantmacher. Two volumes, pp. 374 and 276. 1959. (Translated from the Russian by K. A. Hirsch; Chelsea Publishing Company, New York)

Introduction Fundamentals of biochemical modeling Balance equations Rate laws Generalized mass-action kinetics Various enzyme kinetic rate laws Thermodynamic flow-force relationships Power-law approximation Steady states of biochemical networks General considerations Stable and unstable steady states Multiple steady states Metabolic oscillations Background Mathematical conditions for oscillations Glycolytic oscillations Models of intracellular calcium oscillations A simple three-variable model with only monomolecular and bimolecular reactions Possible physiological significance of oscillations Stoichiometric analysis Conservation relations Linear dependencies between the rows of the stoichiometry matrix Non-negative flux vectors Elementary flux modes Thermodynamic aspects A generalized Wegscheider condition Strictly detailed balanced subnetworks Onsager's reciprocity reactions for coupled enyme reactions Time hierarchy in metabolism Time constants The quasi-steady-state approximation The Rapid equilibrium approximation Modal analysis Metabolic control analysis Basic definitions A systematic approach Theorems of metabolic control analysis Summation theorems Connectivity theorems Calculation of control coefficients using the theorems Geometrical interpretation Control analysis of various systems General remarks Elasticity coefficients for specific rate laws Control coefficients for simple hypothetical pathways Unbranched chains A branched system Control of erythrocyte energy metabolism The reaction system Basic model Interplay of ATP production and ATP consumption Glycolytic energy metabolism and osmotic states A simple model of oxidative phosphorylation A three-step model of serine biosynthesis Time-dependent control coefficients Are control coefficients always parameter independent? Posing the problem A system without conserved moieties A system with a conserved moiety A system including dynamic channeling Normalized versus non-normalized coefficients Analysis in terms of variables other than steady-state concentrations and fluxes General analysis Concentration ratios and free-energy-differences as state variables Entropy production as response variable Control of transient times Control of oscillations A second-order approach A quantitative approach to metabolic regulations Co-response coefficients Fluctuations of internal variables versus parameter perturbations Internal response coefficients Rephrasing the basic equations of metabolic control analysis in terms of co-response coefficients and internal response coefficients Control within and between subsystems Modular approach Overall elasticities Overall control coefficients Flux control insusceptibility Control exerted by elementary steps in enzyme catalysis Control analysis of metabolic channeling Comparison of metabolic control analysis and power-law formalism Computational aspects Application of optimization methods and the interrelation with evolution Optimization of the catalytic properties of single enzymes Basic assumptions Optimal values of elementary rate constants Optimal Michaelis constants Optimization of multienzyme systems Maximization of steady-state flux Influence of osmotic constraints and minimization of intermediate concentrations Minimization of transient times Optimal stoichiometries.

The Regulation of Cellular Systems

The familiar idea of mass action kinetics is extended to embrace situations more general than chemically reacting mixtures in closed vessels. Thus, for example, many reaction regions connected by convective or diffusive mass transport, such as the cellular aggregates of biological tissue, are drawn into a common mathematical scheme. The ideas of chemical thermodynamics, such as the algebraic nature of the equilibrium conditions and the decreasing property of the free energy, are also generalized in a natural way, and it is then possible to identify classes of generalized kinetic expressions which ensure consistency with the extended thermodynamic conditions. The principal result of this work shows that there exists a simply identifiable class of kinetic expressions, including the familiar detailed balanced kinetics as a proper subclass, which ensure consistency with the extended thermodynamic conditions. For kinetics of this class, which we call complex balanced kinetics, exotic behavior such as bistability and oscillation is precluded, so the domain of search for kinetic expressions with this type of behavior, which is of considerable biological interest, is greatly narrowed. It is also shown that the ideas of complex balancing and of detailed balancing are closely related to symmetry under time reversal.

General mass action kinetics

Chemical reaction network structure and the stability of complex isothermal reactors—I. The deficiency zero and deficiency one theorems

Molecular programming aims to systematically engineer molecular and chemical systems of autonomous function and ever-increasing complexity. A key goal is to develop embedded control circuitry within a chemical system to direct molecular events. Here we show that systems of DNA molecules can be constructed that closely approximate the dynamic behavior of arbitrary systems of coupled chemical reactions. By using strand displacement reactions as a primitive, we construct reaction cascades with effectively unimolecular and bimolecular kinetics. Our construction allows individual reactions to be coupled in arbitrary ways such that reactants can participate in multiple reactions simultaneously, reproducing the desired dynamical properties. Thus arbitrary systems of chemical equations can be compiled into real chemical systems. We illustrate our method on the Lotka–Volterra oscillator, a limit-cycle oscillator, a chaotic system, and systems implementing feedback digital logic and algorithmic behavior.

http://www.pnas.org/content/107/12/5393.full.pdf

DNA as a universal substrate for chemical kinetics

In a recent publication (Horn & Jackson [1]) it was shown that complex balancing together with mass action type rate laws ensures certain stability properties of a kinetic system, thereby precluding sustained oscillations, bistability and other types of irregular dynamics. In this paper a necessary condition for complex balancing in general kinetics and necessary and sufficient conditions for complex balancing in mass action systems are derived. A theorem is stated which excludes the occurence of equilibria in certain composition regions of general kinetic systems. For mass action systems it is shown that it is sometimes true that the algebraic structure of the reactions suffices to ensure complex balancing, while in other cases complex balancing occurs only if certain relations between the rate constants are satisfied. The number of these relations, called the deficiency of the mass action system is determined by the algebraic structure of the set of reactions underlying that system.

Necessary and sufficient conditions for complex balancing in chemical kinetics

Two sufficient conditions for improvement of performance by cycling beyond that obtained at the best steady state are compared. It is shown that Condition I, which is derived from relaxed steady-state analysis, is always stronger than Condition II, which results from the maximum principle. That is, in every case in which Condition II guarantees improvement, Condition I does also. However, there are examples where Condition I assures improvement, while Condition II fails to indicate the possibility of greater performance by cyclic operation.

Comparison between two sufficient conditions for improvement of an optimal steady-state process by periodic operation

The approximation theorem of relaxed control has an interesting application in the field of heterogeneous catalysis. For some reaction mechanisms, the selectivity of a catalyst can be increased significantly by operating the catalyst dynamically rather than in the steady state.

An application of the theorem of relaxed control to the problem of increasing catalyst selectivity

The adjoint variables of optimization theory are used in order to investigate the effects of global and local mixing. Global mixing may be caused by bypass, recycle, or general feed bypass. Local mixing is studied by replacing a small part of the reactor with a perfectly mixed cell of equal volume. As an example, a complex reaction system with competing side reactions of different orders is studied in detail.

F. J. M. Horn

Papers

General mass action kinetics

Necessary and sufficient conditions for complex balancing in chemical kinetics

Comparison between two sufficient conditions for improvement of an optimal steady-state process by periodic operation

An application of the theorem of relaxed control to the problem of increasing catalyst selectivity

The use of the adjoint variables in the development of improvement criteria for chemical reactors