Control Theory Tools for Eludicating the Phosphotransfer Network in Rhodobacter Sphaeroides: A Feasibility Study

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Recent advances in molecular biology allow us to explore relationships between microscopic processes. Such studies are useful for determining the structure of underlying biochemical reaction networks so that the mechanisms through which biological systems achieve robust functionality can be identified. Nonetheless, in many instances these studies still lack the resolution sufficient for distinguishing between many plausible interconnections, such as direct and indirect links between molecular components. At this point, mathematical modelling should be used to effectively guide the design of novel experiments and help delineate further biochemical network architectures. A synergy should exist between experiment design and model development, so that not only can realistic models be developed from experimental data, but also new experiments can be designed from models enabling an increased understanding of the system under study. For this to be undertaken and provide a realistic framework for future developments we need to be able to distinguish between the accuracy of different approaches, and for this we need to start with a system that is experimentally well characterised, but with a number of outstanding questions. In this speculative feasibility study in Systems Biology, we propose a 3-stage 'cyclic' procedure that will involve both a control theoretical and an experimental programme in order to understand the phosphotransfer network of R. sphaeroides, using the well-researched phosphotransfer network structure of E. coli as a starting point. This procedure will consist of: (1) Development of various biochemical reaction network models that can explain experimental data. First, two techniques that are proposed will be assessed on the E. coli phosphotransfer network using available experimental data and then both existing and new data will be used for constructing possible phosphotransfer networks for our model organism, R. sphaeroides. One technique is based on control theory and optimization and the other is a hybrid approach which combines statistical modelling and first principles modelling specific to biochemical reactions; (2) Designing the 'best' new experiment with the aim of differentiating between possible R. sphaeroides phosphotransfer network models using control theory tools. These carefully designed experiments will be implemented in the experimental programme; (3) Invalidating some of these models, and proposing new ones for further study - two control theory techniques will be developed for this purpose. This programme will allow comparison of the effectiveness of the two different approaches for parts (1) and (3). If successful, this procedure will lay the groundwork for the development of novel approaches to experimental design across a wide range of biological network problems at a level not attempted previously.