Automated crystal imaging to support discovery science and structure-based drug discovery.

The requested equipment will play a key role in enabling research to illuminate molecular mechanisms across all domains of life and to guide inhibitor design and drug discovery. The instrument in question, the Formulatrix Rock Imager 1000, will be a central element in a pipeline that automates the process by which proteins may be crystallised to allow determination of their 3D structure. Crystallising proteins can require thousands of different conditions to be trialled, and exploiting those crystals to enable the discovery of inhibitors and drugs demands a robust and plentiful supply of protein crystals. To meet this demand, we have established a platform at Newcastle University that streamlines the workflow of setting up crystallization trials, screening crystals and subsequent X-ray data collection.

Key to this workflow is the ability to image, score and analyse large numbers of crystallization trials, which will be provided by the requested equipment. The Formulatrix Rock Imager serves to not only replace a now obsolete instrument but also to extend the capability and capacity of our X-ray crystallography workflow. The new instrument can process hundreds of crystallisation trays to support crystal growth at more than one temperature. It also has improved imaging specifications allowing the visualisation of hard to crystallise proteins. It generates large datasets of tracked results that can be used to guide successive rounds of crystallisation trials, thereby increasing the chances of successfully crystallising the target protein. In this way, the instrument's capabilities also extend the user base to researchers studying challenging proteins and protein complexes as 'high-hanging fruit'. Remote surveillance of crystallization trials from across campus and beyond, enabled by the instrument, will promote collaborative cross-faculty and cross-institutional usage. Integrated and robust informatics also ensures that the data generated by the instrument and the rest of the crystallography platform can be managed and retained for the community in a UKRI-compliant way.

The requested equipment is an essential component of our automated workflow to expedite protein structure solution. The crystals grown in the Formulatrix Rock Imager will then be either imaged in house to determine a protein or protein complex structure or triaged to enable optimal use of our allocated time at the national synchrotron X-ray facility (Diamond Light Source). It will underpin and enhance the university's strength at the forefront of structural biology, and support its cross faculty build in structure-based drug discovery towards novel precision medicine.

We propose to purchase two Formulatrix Rock Imager 1000 'crystal hotels' that together provide for incubating and monitoring protein crystallization trials at two different temperatures. The instrument will enhance our capacity and capability for storing, imaging and evaluating crystallization trays. It will increase our storage capacity to 1000 plates for rapidly assessing thousands of conditions when identifying and optimising crystallization parameters. When used with our Echo500 acoustic dispenser, it will also allow us to crystallise proteins with hundreds of small molecule ligands. It will extend our crystallization capability from low-temperature (4 C) to include 20 C, allowing variation of a key parameter of crystal growth. Moreover, it offers the plate capacity required for multiple rounds of protein-ligand crystallisation to support drug discovery campaigns. Each unit is equipped to visualise crystals by visible and UV light (12 x Zoom visible light optics and fixed Zoom UV options respectively). This capability will provide superior imaging to detect smaller crystals. Rock Maker Imaging software will support the design of screening experiments, viewing and scoring images and report generation. Access to cutting edge software will assist rapid optimisation of crystallization conditions and sample tracking. The option to create user groups and manage access levels will help ensure UKRI compliant data management. Access can be granted to multiple users across campus and beyond to promote collaborative usage. The Rock Imagers will be installed in the university X-ray crystallography facility and will leverage and enhance our considerable investment in complementing technologies that together constitute our crystallography pipeline. This pipeline includes crystallisation plate and drop dispensing robotics and an X-ray source. A matching investment by the university will extend this to allow high-throughput sample mounting with a Shifter instrument.