Proteins are the molecular machines inside every cell, and a new mass spectrometer at the University of Leeds will let scientists watch how these machines bend, stick together, and fall apart in unprecedented detail. Many proteins are floppy, disordered, or form messy clumps that standard techniques like X-ray crystallography or cryo-electron microscopy simply cannot see. This instrument uses two complementary methods—hydrogen-deuterium exchange and native mass spectrometry—to map the shapes and interactions of these difficult proteins, even when they are moving or weakly bound. That fills a critical gap: without this capability, researchers miss the structural basis of how proteins work, malfunction, or can be harnessed. This is fundamental science. It will not directly produce a drug or a diagnostic tomorrow. But the same instrument will be used across projects on antimicrobial resistance, neurodegenerative diseases, virus replication, cardiac disease, and immune dysfunction. By making the equipment available to academic and industrial users across the UK, and training a new generation of scientists, the grant embeds a powerful structural biology tool into the national bioscience infrastructure. Deeper understanding of protein choreography has historically led to breakthroughs in everything from cancer therapies to enzyme design for green chemistry.
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Proteins are the molecular workhorses of the cell and to elicit their biological functions must undertake an intricate molecular choreography by interacting, sometimes weakly and transiently, with other proteins, nucleic acids, small molecules, lipids. It is vital to comprehend the structural basis of these interactions to understand the molecular basis of life, understand dysfunction/disease and to harness the powers of proteins for biotechnology. Several methods now exist to study protein structure, interactions and function, including high-resolution methods such as cryo-electron microscopy, X-Ray crystallography and nuclear magnetic resonance spectroscopy. Structures can even be predicted with high confidence computationally. However, these methods often fail (especially for intrinsically disordered proteins), and they cannot be used to study proteins that form heterogeneous assemblies or describe the motions of malleable proteins. Mass spectrometry-based methods for structural biology can overcome the challenges posed by disordered, heterogeneous and dynamic proteins and their assemblies, and can provide valuable structural information to elucidate the molecular mechanisms underpinning life. Research in the Astbury Centre for Structural Molecular Biology at the University of Leeds aims to understand life in molecular detail. This proposal will embed an advanced mass spectrometer for structural biology within our Mass Spectrometry Facility. This multi-purpose, multi-user instrument will enable protein structural characterisation using two mass spectrometry-based technologies called hydrogen-deuterium exchange and native mass spectrometry. Using the new capabilities of this mass spectrometer we will be able to define the structural arrangement of proteins and their assemblies, understand how structure/interactions change in different disease states, and define ligand binding sites on proteins. These fundamental insights into protein structure and function are uniquely accessible using mass spectrometry-based methods and will provide crucial information to illuminate the molecular basis of life. Crucially, this instrumentation will be equipped with new capabilities for peptide/protein fragmentation that will enable us to define these structural features of proteins and their assemblies in unprecedented detail. We will use this new mass spectrometry equipment in projects spanning the biosciences and biotechnology: this includes projects that will inform on molecular mechanisms underpinning antimicrobial resistance, neurodegenerative diseases, virus replication, cardiac disease, immune dysregulation, and for biopharmaceutical characterisation. By embedding this new mass spectrometer in our Mass Spectrometry Facility, that has a track record of supporting research by a broad and diverse user base, we will make this equipment and these methods available to users across Leeds, as well as to others in academia and industry, to ensure broad impact across bioscience research. We will also deliver a hands-on training programme with the instrument manufacturer, alongside symposia for mass spectrometry-based structural biology, to facilitate new collaborative bioscience research and embed these technologies into the UKs bioscience ecosystem.
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