Collaborative Computational Project for Electron cryo-Microscopy (CCP-EM): 2021 - 2026

The behaviour of living systems ultimately comes down to the interactions of biological molecules inside cells, and understanding these is vital to numerous human efforts, including controlling disease and improving food production. While experimental techniques such as macromolecular crystallography have for many years given detailed information on important molecules in the cell, many classes of molecules are not amenable to this technique. Moreover, as our understanding of pathways in the cell grows, there is increasing interest in the context in which these molecules operate. In other words, where in the cell do these molecules do their job, and which other cellular components are necessary for their function. Electron cryo-Microscopy (cryoEM) provides very useful information here, and bridges the gap between individual molecules and the whole cell. In the most favourable cases, detailed images of assemblies of molecules can be obtained, while at lower resolutions electron tomograms can show internal molecular details from within intact parts of cells or tissues. Advances in instrumentation and data processing led to a significant increase in the quality of cryoEM data, which was characterised in 2014 as the "Resolution Revolution", and recognised by the 2017 Nobel Prize in Chemistry. Consequently there has been a surge in interest in the technique from structural and cellular biologists trying to understand a wide range of biological systems. There has been significant investment in the research infrastructure supporting cryoEM, most notably the establishment of several electron microscope facilities around the country. In the last few years, pharmaceutical companies and biotechnology companies have recognised the importance of cryoEM to their discovery pipelines, and have also begun investing in the area. A key component of this research infrastructure is the computational support to manage the data, process the micrographs, and interpret the data in terms of molecular volumes and/or atomic structures. The Collaborative Computational Project for Electron cryo-Microscopy (CCP-EM) was established during the period 2012 - 2016 to provide this part of the research infrastructure. The proposed project is intended to provide continued support to the cryoEM community. One of the major products of the CCP-EM partnership is a software suite for processing cryoEM data collected at microscope facilities. Individual computer programs in this suite are developed independently, either by members of CCP-EM or collaborators. The role of CCP-EM is to collate these programs into a single suite, develop workflows through the suite, and distribute the suite to practising scientists. When done well, this is a win-win arrangement in which scientists get access to a comprehensive set of software in one place, and methods developers get access to a large user base. It is well known, however, that software rapidly becomes unusable if not actively maintained and it is the responsibility of the core team of CCP-EM to ensure the longevity of software in the suite. We will also expand the scope of the suite. We will improve the tools for validating the structural information obtained, and facilitate the deposition of data in international archives. We will help to drive FAIR principles - that data from cryoEM experiments are accessible and usable to the wider community. We will increase our support for sub-tomogram averaging, a particular technique for obtaining in situ structural information of molecules. Finally, we will make more use of machine learning i.e. advanced algorithms that can learn from the data. All these advances will be tightly coupled with our on-going user training programme, and support for individual methods developers. We will also continue our very popular annual Spring Symposium, which now provides a forum for 300 researchers to share experiences and to develop the cryoEM community.