Diamond Annual Review 2019/20

94 95 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 1 9 / 2 0 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 1 9 / 2 0 XChem Diamond’s XChem facility specialises in X-ray structure-accelerated, synthesis-aligned fragment medicinal chemistry. Integrated into the I04-1 beamline and nearby Lab XChem, offering a highly streamlined process for full X-ray screening experiments. XChem allows up to 1,000 compounds to be screened individually in less than a week (including 40 hours of unattended beamtime). The process covers soaking, harvesting, automatic data collection, and data analysis. This year has seen some exciting developments for the XChem facility. The teamhad already added another 50,000 samples to its experience by September 2019, half the output of the previous four years in eight months, following speedups in the beamline and the consolidation of its core team. Differently from its early operation, from 2019 XChem started offering access through two routes: exploratory projects, where only one eight hour shift is allocated and established projects, for which 32 hours of beamtime are awarded. The expectation is that projects can establish first whether they are ready for a fragment campaign and enrich the case for a full fragment campaign. The programme is now operating with a dedicated 40 hours of beamtime per week, split between commissioning projects, in-house projects and XChem projects. The XChem computational team secured and started implementing an exciting collaboration with Janssen Pharma.This project will take the Fragalysis software, which reviews XChem hits and generates the next follow up series, to the next level with the STFC-IRIS cloud computing infrastructure and new web interfacing technology.The objective is tomake the XChemdatasets widely available through a much more responsive approach to data delivery. From Spring 2019 XChem users were able to run even faster gridscans and X-ray scans using the new beamline electronic controls including the Zebra signal controls box in line with Diamond’s other MX beamlines. Improvements to dataset delivery times kept building 22 datasets per hour in January 2019 to 28 per hour in December 2019 using the new, faster, fully automated X-ray centring mode. Since February 2020, Diamond is ensuring that it is doing everything possible to support researchers in their efforts to discover more about global disease challenges - such as COVID-19 - by working on non-infectious samples. One such research is the CovidMoonshot project where an XChemcampaign on the main protease (M pro ) enzyme from SARS-CoV-2 from theWalsh group at RCaH was undertaken, yielding 91 M pro :fragment complexes deposited on the Protein Data Bank, of which 66 fragment molecules in the M pro binding site. That campaign was used to leverage a consortium effort with Oxford University scientists and the PostEra and Enamine companies to crowdsource designs for a molecule in the hope of shortcutting a process that usually takes years. The non-profit endeavour has yieldedmore than 3,500 designs, with one compound already being hailed as a therapeutic possibility. An effort that delivered results inweeks instead of months, subsequently released in an open science approach. A diagram of the effort undertaken is seen below (credit: David Owen/Walsh group). XFEL Hub Funded initially by theWellcomeTrust and the Biotechnology and Biological Research Council (BBSRC), and now within the annual Diamond operations budget, the XFEL Hub at Diamond aims to provide expertise and support to the UK community engaged in XFEL-related life science research; fromexperimental conception to beamtime proposals, through sample preparations and testing, to XFEL data collection, analysis and publication. The XFEL Hub is integrated within the Macromolecular Crystallography Science Group. Our Diamond based activities continue to include organising and running the block allocation group – Dynamic Structural Biology at Diamond and XFELs – for serial crystallography and time-resolved studies. We participated in user-assisted commissioning of an on-demand picolitre sample delivery method for serial femtosecond crystallography (SFX) in the downstream interaction region at the SPB/SFX Instrument at the European XFEL in Hamburg, Germany. These preliminary results demonstrated on-demand 30 picolitre droplet delivery that was synchronised to European XFEL pulse train with an intra-train frequency of 28 kHz and without wasting sample between pulse trains. The XFEL Hub travel support program for UK scientists participating in XFEL experiments around the world remains open and active. This helped researchers conduct their experiments at the European XFEL, SACLA in Japan, SwissFEL in Switzerland and PAL-XFEL in South Korea as well as in the coming months at the LCLS in the USA.Thus, the XFEL Hub at Diamond and UK scientists are taking advantage of all five facilities. With funding support from the Wellcome, BBSRC/UKRI, The Rosalind Franklin Institute and Diamond Light Source, Dr Orville, Jasper van Thor and Xiadong Zhang organised the ‘Dynamic Structural Biology Workshop: Examining the Life Science Case for a UK XFEL’ on 5th November 2019 at the Francis Crick Institute in London. It attracted nearly 200 participants and included speakers highlighting recent progress with XFELs, cryo-EM and NMR. The workshop was part of the larger effort to develop the science case for a potential UK XFEL. To that end, we are seeking input to the process from across the scientific community. More information can be found at this link: https://www.clf.stfc.ac.uk/Pages/UK-XFEL-science-case.aspx Collaborations The Rosalind Franklin Institute Diamond became a founding member of the Rosalind Franklin Institute, joining ten Universities and UKRI-STFC. A number of joint staff positions already exist between our two organisations. Diamond is a partner in a major initiative of the Franklin, in collaboration with Thermo Fisher Scientific, to develop advanced cryo-electron tomography instrumentation and methods, the AMPLUS project, which is funded in large part by the Office of Life Sciences to the Franklin and Thermo Fisher Scientific. AMPLUS brings in Diamond expertise from the Macromolecular Crystallography and Biological Cryo-Imaging science groups, in particular the electron Bio-Imaging Centre (eBIC) and the Versatile MX micro (VMXm) beamline, as well as leveraging the extensive expertise and experience Diamond has in nanoscale engineering, that is being brought to bear to develop a vision for next generation electron tomography and electron diffraction instruments. Another key contribution of Diamond to this collaboration is partnering in the development of electron imaging simulation software that not only assists in the optimisation of analysis software, but can also drive the specification and design of electron microscope instrumentation. Diamond’s substantial experience in nanoscale engineering is being brought to bear in developing a vision for next generation electron tomography and electron diffraction instruments. A major Diamond undertaking in this area will be HeXI (Hybrid electron-X-ray Instrument), a dedicated electron diffraction beamline for sub- micron macromolecular and small molecule crystallography. In future we expect that the Franklin will form a productive symbiotic relationship with Diamond, whereby the Franklin is able to address high-risk high-reward challenges in the life sciences and have Diamond partner in these novel developments turning them into user accessible facilities, while using its wealth of expertise in instrumentation, methods, software development and high performance computing to feed into Franklin developments. Diamond looks forward to a long and productive partnership. The University of Manchester at Harwell The University of Manchester at Harwell (UoMaH) is hosted by Diamond as part of the partnership The University of Manchester (UoM) is setting up with facilities at Harwell. UoMaH provides the interface with the Harwell national facilities, enabling UoM researchers to access world-class research at Diamond and all the Science and Technology Facilities Council (STFC) facilities at Harwell, including the ISIS Neutron and Muon Source (ISIS), Scientific Computing Department (SCD) and the Central Laser Facility. UoMaH iscomprisedofcoreadministrativeandtechnicalteamsandresearch fellows and their groups. The core technical team specialises in developing sample environments and equipment in support of experiments, involving high risk materials and extreme sample environments, fielded at the national facilities. UoMaH research fellows, are affiliated with different departments within the University’s Faculty of Science and Engineering, and pursue research in critical themes to both the University and the facilities. Currently, UoMaH has a growing contingent of fellows based at Harwell; the two fellows working on resilience and catalysis are sponsored by Diamond and the one fellow working on fusion sponsored by ISIS. Alongside them, five further fellows and their groups are based in Manchester. The fellows strengthen the University’s link with Harwell by bringing their research, networks and new users from industry and Faculty academics to Diamond. In the past year, UoMaH has built new, and deepened existing, connections with Diamond and the other Harwell facilities by engaging in Harwell events and hosting colloquia. The last of these brought together over 50 people from across campus and was transmitted virtually back to Manchester. In May 2019, UoMaH was joined by representatives from Diamond, ISIS and SCD at the first of their annual roadshows in Manchester. Senior staff from the University, STFC and Diamond introduced the new collaboration to an audience of university staff and key workers from Harwell. Case studies illustrated the research undertaken at ISIS, SCD and Diamond and participants contributed to sandpit sessions identifying future opportunities and areas for development for UoMaH. The event has stimulated attendees’ engagement in new beamtime experiments and requests for new specialist equipment from the UoMaH core team. We are engaging with Diamond in our teaching and learning mission; in June 2019, UoMaH welcomed 33 PhD students, to Diamond and ISIS, as part of the Materials for Demanding Environments and Advanced Metallic Systems CDTs. Finally, in November 2019 UoMaH hosted a meeting at Diamond, linking up current capabilities at Harwell national facilities with researchers working on nuclearmaterials.AttendeesfromeightUKuniversitiesandnationallaboratories discussed near term activities, new sample environment requirements and the means to work together to achieve these demanding experiments. UoMaH will work with Diamond and the Dalton Nuclear Institute to organise a second event to develop some of these ideas further and to explore more ambitious projects for the future. UK Catalysis Hub Catalysis is a core area of contemporary science, engineering and technology that has substantial economic and societal impact, and is of significance to the UK’s Industrial Strategy, making it a strong area of focus for Diamond. The physical home of the UK Catalysis Hub – a national network with over 40 collaborating universities – is located next to Diamond at the Research Complex at Harwell (RCaH). It provides a platform for researchers towork collectively, and to gain frequent access to the synchrotron, alongside other facilities at Harwell. The UK Catalysis Hub was established in 2013 with funding from the Engineering and Physical Sciences Research Council (EPSRC). An additional £14 million in funding from the EPSRC was committed in October 2018. The Hub seeks to coordinate, promote and advance the UK catalysis research portfolio. The project has four new interrelated themes: Core • Optimising, Predicting and Designing New Catalysts • Catalysis at theWater Energy Nexus • Catalysis for the Circular Economy and Sustainable Manufacturing The Hub promotes a whole system approach to the study of catalysis combined with high throughput, which allows optimal experiments to be carried out which shorten the path to development of commercially useful products and promote the UK catalysis effort and expertise on a global stage. One of the main continued benefits of the Catalysis Hub is sustained access to a synchrotron radiation source. Professor Andrew Dent, Diamond’s Deputy Director of Physical Sciences, explains, “The UK Catalysis Hub has a Block Allocation Group (BAG) on the X-ray Absorption Spectroscopy (XAS) beamline B18 at Diamond. The Hub coordinates the experiments they perform in that time, which allows them to more effectively carry out their research.” This access route increases the efficiency of data acquisition and allocates small amounts of time for proof of concept investigations and rapid access for in situ and ex situ applications before a full study starts. Applications are judged by a panel of expert academics and beamline scientists, who consider (i) the quality of the underpinning science, (ii) the likely success of the experiments, (iii) bringing in new users of synchrotron radiation, and (iv) coordinating time effectively to maximise efficiency. This opportunity is open to every academic working in catalysis in the UK. Timeline of crystallographic fragment screen. Credit David Owen/Walsh team in Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease, Nature Comms (accepted).

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