A new detector will allow UK scientists to capture snapshots of proteins in action at timescales of tens of microseconds—a speed currently impossible at the Diamond Light Source synchrotron. Many biological processes, such as enzymes breaking down antibiotics or proteins in the eye reacting to UV light, happen in the range of 10 milliseconds to 10 microseconds. Existing photon-counting detectors cannot record X-ray diffraction data accurately at these speeds, forcing researchers to rely on expensive, distant X-ray free-electron lasers (XFELs) that offer infrequent access. This gap means crucial intermediate structures—like those in enzymes driving the global nitrogen cycle—remain invisible without XFEL time. The integrating Jungfrau 9M detector, installed alongside an existing detector on beamline I24, will let the UK community perform time-resolved serial synchrotron crystallography (SSX) at these faster timescales. If successful, it will shift many experiments from XFELs to a regularly accessible synchrotron, lowering the barrier for iterative studies. This could accelerate understanding of antimicrobial resistance, industrial biotechnology, cataract formation, and agricultural nitrogen cycling—without requiring a trip to a multi-billion-pound laser facility.
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The ability to determine time resolved structures of macromolecules carrying out their functions is opening a new frontier in life sciences. A key technique is time resolved serial X-ray crystallography whereby many tiny crystals are sequentially delivered into the X-ray beam at a defined time point after an enzyme reaction or other biological process is initiated. By varying the time delay between initiation and data collection, a high-resolution time-dependent molecular movie of the protein is produced. X-ray Free Electron Lasers (XFELs) produce extremely short (fs) X-ray pulses enabling time delays as short as femtoseconds. Such experiments are highly challenging due to difficulty in obtaining beamtime (and infrequent access) at expensive distant facilities, large teams required, unfamiliar sample preparation and challenging data analysis. Serial synchrotron crystallography (SSX) is democratising time-resolved structural biology by addressing these challenges. SSX can be offered regularly to many more research teams at more local facilities, greatly lowering the entry barrier and can in principle address most timescales of relevance to biology, except the very fastest reactions which inherently require XFEL sources. Many biological processes such as enzyme catalysis occur in the range 10ms-10 microseconds: a time domain currently inaccessible to SSX at Diamond. Increased fluxes at synchrotrons allow diffraction to be obtained in ever thinner time-slices but this cannot be accurately recorded using the current generation of photon counting detectors. This proposal will fund an integrating detector for time resolved macromolecular crystallography (MX) at Diamond allowing the UK community to directly access tens of microsecond-plus timescales using SSX. This would significantly increase UK capabilities/reach of the UK dynamic structural biology community. Key advantages include carrying out many currently XFEL-only experiments using more accessible synchrotrons, with regular access allowing for iterative experiments using a well-defined X-ray source. We seek support to purchase a Jungfrau 9M integrating detector enabling full exploitation of the capability of Diamond to access shorter time regimes. The detector will be installed alongside an existing counting detector at the recently upgraded beamline I24 to take advantage of world leading sample delivery systems and data processing expertise. Our aims include: Integrate the detector into a world leading synchrotron beamline Use samples from the coinvestigator team to provide new insights into enzyme mechanism in a variety of systems by obtaining faster reaction time points Following commissioning offer the use of the Jungfrau detector broadly to the UK and international structural biology academic and industrial communities through Diamond's peer-reviewed and proprietary access mechanisms The Jungfrau 9M will enable us to transcend the current limitations of experiments on multiple biological systems studied by the coinvestigators together with the broader UK and international communities. Projects from the applicant team that would immediately benefit include: Proteins important in antimicrobial resistance Iron containing proteins relevant to industrial biotechnology Understanding how exposure of a protein in the human eye to UV light leads to cataract formation Enzymes involved in the global nitrogen cycle (and so highly relevant to agriculture) where crucial intermediate structures are currently inaccessible without XFEL access.
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