Dynamics, Gating and Opening in Enzyme Catalysis

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The present application aims to get to the heart of fundamental, yet unanswered, questions that are critical to developing our understanding of how enzymes work. Enzymes, which are normally protein-based, control the rate at which almost all chemistry occurs in living systems. Understanding enzyme activity is a high priority - it is at the core of therapeutic intervention, industrial biotechnology, and synthetic biology. The controlled manipulation of enzyme activity is one of the key elements targeted in each of these areas of research. Enzyme activity has been studied for many decades and many paradigms have evolved but, very recently, tools have been developed that allow the testing of those paradigms with unprecedented levels of detail. Arguably foremost among these tools is NMR spectroscopy, which allows the observation of the structure, electronics and dynamics within enzymes at the level of individual atoms. A proper understanding of all of these elements and their interplay is crucial to manipulating enzyme activity, and with observation powers at this level of detail, paradigms are shifting. In this study we will address questions that are fundamental to the activity of almost all enzymes, namely what controls how fast the chemistry occurs, what makes an enzyme carry out one reaction against another, and what determines how well it binds to the chemicals on which it acts. To achieve this we will study the behaviour of an enzyme that moves phosphate groups around glucose. Enzymes that move phosphate groups lie at the heart of every system in living organisms - in the storage, maintenance and expression of genetic information, in metabolism, communication, cell architecture, differentiation, and homeostasis. We will develop new models based on the behaviour an archetypal enzyme that delivers very high quality measurements, which can then be translated to the enzymes that are common targets in therapeutic, industrial biotechnology and synthetic biology programmes.