Diamond Annual Review 2020/21

15 14 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 2 0 / 2 1 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 2 0 / 2 1 Macromolecular Crystallography Group Dave Hall, Science Group Leader B iological interactions underpin and can undermine the processes of life, as exemplified this year by the SARS-CoV-2 pandemic. The technique of Macromolecular Crystallography (MX) uses X-rays to reveal the details of biological molecules at atomic and temporal scales and is an enabler in our understanding of the processes and interactions of life. Seven beamlines (I03, I04, I04-1, I23, I24, VMXi and VMXm), alongside the XChem fragment screening facility, the UK X-ray Free Electron Laser (XFEL) Hub and the Membrane Protein Laboratory (MPL) at Diamond Light Source are dedicated to exploiting the technique of MX for the benefit of the worldwide structural biology community. The onset of the COVID-19 pandemic in early 2020 drove significant changes for MX user operations and beamline improvements. One of the biggest changes this year has been howusers access MX beamtime. Historically a six-month schedule was published and users prepared samples for their scheduled slots. With lockdowns affecting user lab access and Diamond machine operations, we transitioned quickly to a responsive mode of user rapidly collect 1s datasets. The crystallisation facility associated with VMXi has beenworkingwith commissioning users to grow crystals fromprotein provided by them for use at VMXi. Data collections are configured remotely by the users and run automatically by the beamline. Over 2021, we expect to steadily increase access to VMXi in line with capabilities within the crystallisation facility and as users can access their labs and site as lockdowns retreat. This year the Long Wavelength beamline, I23, implemented a significant upgrade for delivering their thermally conductive sample mounts into the in vacuum experimental end station. The new cryo-transfer system provides a user-friendly way of transferring the sample mounts, whilst maintaining samples at cryogenic temperatures within the vacuum environment. It has been successfully commissioned by the I23 teamwith user samples throughout the restrictions during the pandemic and several difficult structures could be solved. During the pandemic, I04-1 and the XChem facility prioritised the seven user-submitted COVID-19 projects. By the last quarter of the year, the full focus had returned to previously scheduled academic and industry experiments. Remarkably, XChem staff managed to accommodate all projects despite having to perform all on-site experimental work. This year, two projects have been signed off that will transform the beamline's capabilities. Firstly, a new Eiger2 XE 9M detector has been ordered and delivered that has a frame rate up to 20 times higher than the existing detector. This will be installed in the very near future. Secondly, to fully exploit the detector capabilities, a new hybrid permanent magnet undulator insertion device has been approved that will bring a significant increase in flux. Together these will increase the throughput of I04-1, allowing it to run experiments on weaker diffracting crystals and providing increased opportunities for the fragment-based drug design community. Work has continued on MX needs for Diamond-II (proposed upgrade programme) throughout 2020. Over the last year, proposals for flagship beamlines and projects for Diamond-II have been put forward in conjunction with user community support for review by Diamond’s science and industrial advisory boards (SAC and DISCo). Beamline I04-1 cannot easily remain in its current position in the new Diamond-II lattice and it is proposed to build a new beamline with significantly enhanced features at a new position in the ring. The Microfocus beamline, I24, proposed upgrading and updating its microfocus capabilities, alongside further improving its SSX offering. Both of these proposals were highly regarded by SAC-DISCo and will proceed as part of the Diamond-II project. User community support for both proposals was key to their success and is very much appreciated. In parallel to supporting user experiments and significant upgrades, we have also continued with our remit to train future generations of structural biologists. This year our annual Diamond-CCP4 training course in crystallography, which includes data collection at the MX beamlines for the students, was run completely remotely over two weeks for the first time. Following its success, we provided beamtime and support to a CCP4-South Africa crystallographic school, again remotely over two weeks. Finally, it must not go unrecognised that an exceptional year was underpinned by the remarkable staff of the MX group, support groups and wider Diamond teamwho all stepped up in many ways to support our MX user community. beamtime. Experiments are fully remote, via automated unattended data collection or undertaken by Diamond staff (I23, XChem fragment screening, VMXi crystallisation, Serial Synchrotron Crystallography (SSX)). These are scheduled once user samples are delivered to site, typically within a week. User feedback for this mode of access has been very supportive and we will incorporate this into our future offering. In 2020 COVID-19 research was prioritised, with a special rapid access user call opened early on. Time has been awarded for scientists from across the world studying a range of SARS-CoV-2 targets. They have taken advantage of access to the high-throughput beamlines I03 and I04 for rapid turnaround of high-resolution structures, room temperature studies on I24 and VMXi, drug repurposing studies across the MX beamlines and the XChem I04-1 facility for large scale fragment screening, which in itself has kickstarted the COVID Moonshot project – a crowdsourcing molecular design initiative looking for an antiviral against the main protease. The XFEL Hub has coordinated user remote access experiments on targets from SARS-CoV-2 at XFELs around the world. Much of this work has been possible due to continued access to theMPL, crystallisation facilities and Diamond research support staff. The outcome of this research is already evidenced by the high number of structures released to the Protein Data Bank (PDB) and speed with which papers have been published. Fully automated Unattended Data Collection (UDC) was introduced as a new mode of operation in 2020, firstly on I03 and then rolled out to I04 and I04-1. This provides fast and efficient data collection with no user interaction with the beamlines, enabling users to focus on their science and not be tied to collecting data, often at anti-social hours or when access to offices is limited during the pandemic. Users prepare samples for shipment with associated diffraction plans and then ship their samples. Once samples arrive at Diamond they are queued to an appropriate beamline and data collected at the earliest possible opportunity. This fits in well with the responsive mode of access to Diamond MX beamlines, with turnaround times typically within a week of arrival. Many academic and industrial user groups are now using this access method routinely, with tens of thousands of high quality data sets collected in 2020 alone. Despite restrictions in working practices throughout the pandemic, we have continued to prioritise essential upgrades to ensure beamlines remain state of the art. The Microfocus beamline I24 installed a cryogenic permanent magnet undulator providing higher fluxes, in particular at higher energies. This is linked to the installation of a detector optimised for use at these high energies – the first CdTe Eiger2 9M. Together these upgrades provide the opportunity to explore further the possibilities of using higher energies for data collection, in particular from the small crystals typically used for SSX. VMXi and VMXm were in the process of moving towards user operations prior to the pandemic and this progress has been slowed, however the sub- micron focus beamline VMXm recently installed an identical detector to that installed on I24 earlier in 2020. As further commissioning and user operations begin on VMXm this new detector, alongside its unique electron microscope equipped end station, will enable users to investigate the smallest of crystals to elucidate structures not previously tractable. The room temperature in situ beamline VMXi saw a new goniometer successfully installed, which now enables the beamline to accurately and The onset of the COVID-19 pandemic in early 2020 drove significant changes for MX user operations and beamline improvements. One of the biggest changes this year has been howusers access MX beamtime.

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