Metabolic Futile Cycles and Their Functions: A Systems Analysis of Energy and Control

It has long been hypothesized that futile cycles in cellular metabolism are involved in the regulation of biochemical pathways. Following the work of Newsholme and Crabtree, we develop a quantitative theory for this idea based on open-system thermodynamics and metabolic control analysis. It is shown that the {\it stoichiometric sensitivity} of an intermediary metabolite concentration with respect to changes in steady-state flux is governed by the effective equilibrium constant of the intermediate formation, and the equilibrium can be regulated by a futile cycle. The direction of the shift in the effective equilibrium constant depends on the direction of operation of the futile cycle. High stoichiometric sensitivity corresponds to ultrasensitivity of an intermediate concentration to net flow through a pathway; low stoichiometric sensitivity corresponds to super-robustness of concentration with respect to changes in flux. Both cases potentially play important roles in metabolic regulation. Futile cycles actively shift the effective equilibrium by expending energy; the magnitude of changes in effective equilibria and sensitivities is a function of the amount of energy used by a futile cycle. This proposed mechanism for control by futile cycles works remarkably similarly to kinetic proofreading in biosynthesis. The sensitivity of the system is also intimately related to the rate of concentration fluctuations of intermediate metabolites. The possibly different roles of the two major mechanisms for cellular biochemical regulation, namely reversible chemical modifications via futile cycles and shifting equilibrium by macromolecular binding, are discussed.Comment: 11 pages, 5 figure

Evolving networks with disadvantaged long-range connections

We consider a growing network, whose growth algorithm is based on the preferential attachment typical for scale-free constructions, but where the long-range bonds are disadvantaged. Thus, the probability to get connected to a site at distance $d$ is proportional to $d^{-\alpha}$, where $\alpha$ is a tunable parameter of the model. We show that the properties of the networks grown with $\alpha <1$ are close to those of the genuine scale-free construction, while for $\alpha >1$ the structure of the network is vastly different. Thus, in this regime, the node degree distribution is no more a power law, and it is well-represented by a stretched exponential. On the other hand, the small-world property of the growing networks is preserved at all values of $\alpha$.Comment: REVTeX, 6 pages, 5 figure

Edge overload breakdown in evolving networks

We investigate growing networks based on Barabasi and Albert's algorithm for generating scale-free networks, but with edges sensitive to overload breakdown. the load is defined through edge betweenness centrality. We focus on the situation where the average number of connections per vertex is, as the number of vertices, linearly increasing in time. After an initial stage of growth, the network undergoes avalanching breakdowns to a fragmented state from which it never recovers. This breakdown is much less violent if the growth is by random rather than preferential attachment (as defines the Barabasi and Albert model). We briefly discuss the case where the average number of connections per vertex is constant. In this case no breakdown avalanches occur. Implications to the growth of real-world communication networks are discussed.Comment: To appear in Phys. Rev.

Signatures of small-world and scale-free properties in large computer programs

A large computer program is typically divided into many hundreds or even thousands of smaller units, whose logical connections define a network in a natural way. This network reflects the internal structure of the program, and defines the ``information flow'' within the program. We show that, (1) due to its growth in time this network displays a scale-free feature in that the probability of the number of links at a node obeys a power-law distribution, and (2) as a result of performance optimization of the program the network has a small-world structure. We believe that these features are generic for large computer programs. Our work extends the previous studies on growing networks, which have mostly been for physical networks, to the domain of computer software.Comment: 4 pages, 1 figure, to appear in Phys. Rev.

The spread of epidemic disease on networks

The study of social networks, and in particular the spread of disease on networks, has attracted considerable recent attention in the physics community. In this paper, we show that a large class of standard epidemiological models, the so-called susceptible/infective/removed (SIR) models can be solved exactly on a wide variety of networks. In addition to the standard but unrealistic case of fixed infectiveness time and fixed and uncorrelated probability of transmission between all pairs of individuals, we solve cases in which times and probabilities are non-uniform and correlated. We also consider one simple case of an epidemic in a structured population, that of a sexually transmitted disease in a population divided into men and women. We confirm the correctness of our exact solutions with numerical simulations of SIR epidemics on networks.Comment: 12 pages, 3 figure

Correlations in Scale-Free Networks: Tomography and Percolation

We discuss three related models of scale-free networks with the same degree distribution but different correlation properties. Starting from the Barabasi-Albert construction based on growth and preferential attachment we discuss two other networks emerging when randomizing it with respect to links or nodes. We point out that the Barabasi-Albert model displays dissortative behavior with respect to the nodes' degrees, while the node-randomized network shows assortative mixing. These kinds of correlations are visualized by discussig the shell structure of the networks around their arbitrary node. In spite of different correlation behavior, all three constructions exhibit similar percolation properties.Comment: 6 pages, 2 figures; added reference

A Taxonomy of Causality-Based Biological Properties

We formally characterize a set of causality-based properties of metabolic networks. This set of properties aims at making precise several notions on the production of metabolites, which are familiar in the biologists' terminology. From a theoretical point of view, biochemical reactions are abstractly represented as causal implications and the produced metabolites as causal consequences of the implication representing the corresponding reaction. The fact that a reactant is produced is represented by means of the chain of reactions that have made it exist. Such representation abstracts away from quantities, stoichiometric and thermodynamic parameters and constitutes the basis for the characterization of our properties. Moreover, we propose an effective method for verifying our properties based on an abstract model of system dynamics. This consists of a new abstract semantics for the system seen as a concurrent network and expressed using the Chemical Ground Form calculus. We illustrate an application of this framework to a portion of a real metabolic pathway