Protein Choreography

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.

Impact Goal: To create new opportunities for drug discovery and biotechnology by building new tools to understand how protein molecules move.

Beneficiaries
Private sector: Pharmaceutical companies, for example multi-nationals with major R&D presence in the UK, like AstraZeneca and GSK. Private sector biotechnology companies, including producers of enzyme drugs, such as Ipsen and also antibody discovery organisations, such as Kymab and Genentech. Vendors of mass spectrometry instrumentation, such as Waters, who have a major R&D base in Manchester, UK. Also Thermo-Fisher, whose hydrogen/deuterium-exchange mass spectrometry is developed as part of an Integrated Structural Biology team, which is well aligned with the aims of my research programme. Many of these vendors offer a bespoke software solution to run and analyse experiments and the software advances made by myself in partnership with The Alan Turing Institute would be anticipated to be highly attractive to these vendors, but also to the dedicated producers of mass spectrometry and structural biology software, like GeneData, Sierra Analytics and Schrodinger.
The data science and artificial intelligence community: The data science community comprises public sector stakeholders, such as The Alan Turing Institute and intelligence agencies (GCHQ; MI5), as well as private sector organisations, which includes large global companies like Google, but also smaller start-up ventures in the UK, like MonolithAI.
People whose lives are impacted by genetic disease: Sufferers of disease and those that care for them, stand to benefit from the objectives of my work, including those living with cystic fibrosis, Tay-Sachs, phenylketonuria and sickle cell anaemia.
Educators and students: Science educators in the public sector, ranging from early school age through to popular science communication.
The arts: Communities of artists and scientists at the science/art-interface, such as artist Gemma Anderson and academic scientist Dr Ljiljiana Fruk.

Impact Objectives
1. To enable the direct discovery of emergent classes of medicine in the pharmaceutical industry ('allosteric' drugs), providing proof of principle by 2027 for a secondary screening technology that can be deployed in pharmaceutical companies, such as AstraZeneca, to create new drug products.
2. To create protocols and tools that create data-driven models of protein movement during catalysis and in response to drugs, enabling new products to be discovered by pharmaceutical and biotechnology organisations.
3. To generate new paradigms and tools for the efficient acquisition and visualisation of time-resolved data for analysts in public/private sectors who work with sparse, noisy, expensive and high-dimensional data.
4. An ultimate goal of this work is to improve the quality of life for those affected by genetic disease by developing new and efficient base editing tools as personalised therapies.
5. To transform the ways we have of knowing what is meant by movement and change for molecules, broadening the understanding of molecular science within the art community by developing art/science tools, methods and artistic works that will explore how we can view biology as a process. I will contribute to exhibitions, published books and manuscripts and drawing workshops. The development of novel educational tools is of particular benefit to engage school aged students with nanoscale science.