Scalable rule-based modelling of allosteric proteins and biochemical networks

Much of the complexity of biochemical networks comes from the information-processing abilities of allosteric proteins, be they receptors, ion-channels, signalling molecules or transcription factors. An allosteric protein can be uniquely regulated by each combination of input molecules that it binds. This "regulatory complexity" causes a combinatorial increase in the number of parameters required to fit experimental data as the number of protein interactions increases. It therefore challenges the creation, updating, and re-use of biochemical models. Here, we propose a rule-based modelling framework that exploits the intrinsic modularity of protein structure to address regulatory complexity. Rather than treating proteins as "black boxes", we model their hierarchical structure and, as conformational changes, internal dynamics. By modelling the regulation of allosteric proteins through these conformational changes, we often decrease the number of parameters required to fit data, and so reduce over-fitting and improve the predictive power of a model. Our method is thermodynamically grounded, imposes detailed balance, and also includes molecular cross-talk and the background activity of enzymes. We use our Allosteric Network Compiler to examine how allostery can facilitate macromolecular assembly and how competitive ligands can change the observed cooperativity of an allosteric protein. We also develop a parsimonious model of G protein-coupled receptors that explains functional selectivity and can predict the rank order of potency of agonists acting through a receptor. Our methodology should provide a basis for scalable, modular and executable modelling of biochemical networks in systems and synthetic biology

Open doors and closed frontiers: the limits of American empire

This article argues that the contemporary American empire displays two structural limits. The first refers to geographical limits. As opposed to most of its imperial predecessors, the logic of contemporary US power militates against direct, territorial domination as a means of sustaining global hegemony. The second limitation, tightly linked to this first one, is that of power defined in a conventional sense as the capacity to secure outcomes. Consequently, since 1945 the USA has generally projected its global power through open doors (capitalist markets) and closed frontiers (sovereign territorial states). The article explores the peculiar limits to US empire with reference to two of its principal western precursors — the Roman and British empires — and concludes that the recent invasion and occupation of Iraq highlights the perils of an American strategy that seeks to conquer territories militarily and politically control their populations