Protein Choreography

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The processes of life are dynamic - it is change on a molecular level that enables us to grow and move, but also to become ill and treat disease. Just as the shape and posture of our body can determine our readiness to perform a task, the structure and conformation of a protein molecule can determine its function or activity. It is the ability for proteins to dynamically and rapidly reconfigure that underpins many critical activities in biology, disease and medicine.However, we are currently limited to study proteins, including many important enzymes, at high resolution in space or time - but not both. Static structural models have contributed to major advances, such as in gene editing technology, based on the reprogramming of the enzyme 'CRISPR/Cas9'. This structural information is also crucial for drug discovery, accurately guiding design and optimisation efforts.These are major new applications that rely on precisely controlling dynamic changes in protein structure. These aims - and our understanding of fundamental biology - will be greatly advanced by bridging high resolution information in both time and space.My research will pioneer an integrated experimental and computational approach to determine with unprecedented spatio-temporal resolution how enzymes are dynamically regulated and how they catalyse chemical reactions. We now have a unique opportunity to make measurements of the structural perturbations in large enzymes both with high structural resolution (per amino acid building block) and high temporal resolution (per millisecond). The information that we gain will be used to build high resolution dynamic structural models in which individual features reconfigure according to their individual rates, determined experimentally with millisecond and amino acid precision. This work will focus on two areas of recent high profile success in developing tools for biotechnology and medicine which depend on the exquisite control of enzyme dynamic structural changes. (i) Gene editing: There is a growing effort to engineer CRISPR/Cas9 enzymes to improve their efficiency and to create entirely new tools for targeted mutation of the genome in situ. This has potentially broad application in research, but also to specifically treat genetic diseases. We will study gene editing enzymes to provide mechanistic insight to explain their behaviour and to guide the development of variants with improved activities. (ii) Allosteric drug discovery. There has been major recent investment by both big pharma and by venture capital/biotechnology partnerships to discover 'allosteric' drugs that control enzyme function by controlling the protein conformation. These drugs have potential benefits in selectivity and the ability to modify otherwise intractable targets in disease. We will ascertain whether the new millisecond time-resolved measurements that we will develop can differentiate signatures of allosteric regulation and thus form the basis of a direct screen for allosteric drugs.This research programme brings together expertise in building novel experimental methods, cutting edge data science approaches, development of new software tools and a direct relevance to fundamental biology and applications in biotechnology and drug discovery.