## 5 The Specific Case of DnaA in the _E. coli_ Cell Cycle
### Ribosomes  
Interactions between DnaA and ribosomal protein L2 (or truncated L2) have been shown to inhibit initiation _in vitro_ and it has been proposed that DnaA may act as a sensor coordinating initiation with cell growth [92]. However, interpreting this result in the context of Dualism is not straightforward. It is not in line with a ribosomal hyperstructure acting as an intensity sensor because, the prediction is that if DNA is becoming limiting, redundant ribosomes may start to accumulate, become inactive and perhaps release L2 (we are trying here to see past layers of sophisticated feedback controls) which should stimulate initiation. The opposite occurs. It is not in line with quantity sensing either because, again, the prediction is that if ribosomes accumulate as equilibrium structures, release of L2 should again stimulate initiation. Although no hypothesis should be required to explain all the data, Dualism might offer an explanation: the signal that results from the combination of intensity and quantity sensing and that initiates replication also then prevents further initiation (along the lines of the Regulatory Inactivation of DnaA in which, after initiation, the Hda protein plus DNA promote the hydrolysis of active ATP-DnaA to inactive ADP-DnaA [71]). So the prediction from Dualism would then be that in the conversion of equilibrium to non-equilibrium structures--and the consequent redeployment of ribosomes--L2 is released to contribute the inhibition of further initiations. Finally, given that L2 also interacts with a heat shock protein, HtpG, it is conceivable that its inhibition of DnaA is simply a response to stress rather than part of regulation in an unperturbed cycle [135]. Many levels of classical regulatory systems have been glossed over in this and other sections. One of the most important is growth rate control. In the rest of this subsection, we suggest how growth rate control might fit into our scenario. Growth rate control is about the major changes that occur in Enterobacteriaceae as they adapt to environments that differ in their nutritional richness. The mechanisms involved in growth rate control might therefore be expected to be involved in the changes that we propose occur during the cell cycle. As a result of growth rate control, Enterobacteriaceae change as the rate of balanced growth increases: they become larger, have more replication forks per chromosome and have an increased RNA:mass ratio (primarily because more ribosomes are formed per unit mass) [34,56,136-138]. This increase in ribosomes affects the size and topology of the ribosomal hyperstructure [26,56]. One of the major players in control rate control is (p)ppGpp [139]. ppGpp and ppGpp are phosphorylated derivatives of GTP and GDP, respectively, obtained when a ribosome engaged in translation encounters an uncharged tRNA [139]. (p)ppGpp is an important link in coupling nutrient availability with many aspects of bacterial physiology including growth rate control, adaptation, secondary metabolism, survival, persistence, motility, biofilm formation, development, competence, virulence and initiation of DNA replication and cell division. In section 5.4, the phenomenon of ion condensation was described in terms of positive counterions condensing onto negative linear polymers: it can be applied equally well to negative counterions condensing onto positive linear polymers. In _E. coli_, high levels of (p)ppGpp inhibit growth and change gene expression to reduce unnecessary activities in non-growing cells whilst excessively low levels result in cells responding inadequately to nutritional stress [139]. In the context of a role for ion condensation in life on the scales of equilibria, we might expect (p)ppGpp to decrease the average NE/E ratio.