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

分子生物学的最新进展使我们能够探索微观过程之间的关系。这些研究对于确定潜在的生化反应网络的结构是有用的，从而可以识别生物系统实现强大功能的机制。尽管如此，在许多情况下，这些研究仍然缺乏足够的分辨率来区分许多可能的相互联系，例如分子组分之间的直接和间接联系。在这一点上，数学建模应该被用来有效地指导新实验的设计，并帮助描绘进一步的生化网络架构。实验设计和模型开发之间应存在协同作用，这样不仅可以从实验数据中开发出现实的模型，而且可以从模型中设计新的实验，从而提高对所研究系统的理解。为了实现这一点，并为未来的发展提供一个现实的框架，我们需要能够区分不同方法的准确性，为此，我们需要从一个实验上很好表征的系统开始，但有一些悬而未决的问题。在系统生物学的这一推测性可行性研究中，我们提出了一个3阶段的“循环”程序，该程序将涉及控制理论和实验程序，以了解R的磷酸转移网络。sphaeroides的磷酸转移网络结构。大肠杆菌作为起点。该程序将包括：（1）开发可以解释实验数据的各种生化反应网络模型。首先，提出的两种技术将在E.大肠杆菌的磷酸转移网络，然后现有的和新的数据将用于构建可能的磷酸转移网络为我们的模式生物，R。sphaeroides一种技术是基于控制理论和优化，另一种是一种混合的方法，它结合了统计建模和第一原理建模特定的生化反应;（2）设计“最好的”新实验的目的是区分可能的R。sphaeroides磷酸转移网络模型使用控制理论工具。这些精心设计的实验将在实验方案中实施;（3）使其中一些模型无效，并提出新的模型供进一步研究-为此目的将开发两种控制理论技术。该方案将允许比较第（1）和第（3）部分两种不同方法的有效性。如果成功的话，这一过程将奠定基础，为开发新的方法，实验设计在广泛的生物网络问题的水平没有尝试过。

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.