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

生命系统的行为最终归结为细胞内生物分子的相互作用，了解这些相互作用对于人类的许多努力至关重要，包括控制疾病和提高粮食产量。虽然实验技术，如大分子结晶学，多年来提供了关于细胞中重要分子的详细信息，但许多类别的分子不适用于这种技术。此外，随着我们对细胞内途径的了解不断加深，人们对这些分子的工作环境也越来越感兴趣。换句话说，这些分子在细胞中的哪里发挥作用，以及哪些其他细胞成分是它们发挥功能所必需的。电子冷冻显微镜在这里提供了非常有用的信息，并在单个分子和整个细胞之间架起了一座桥梁。在最有利的情况下，可以获得分子组装的详细图像，而在较低分辨率的电子断层图像可以显示细胞或组织完整部分的内部分子细节。仪器和数据处理的进步导致低温电子显微镜数据质量的显著提高，这在2014年被描述为“分辨率革命”，并得到2017年诺贝尔化学奖的认可。因此，结构和细胞生物学家对这项技术的兴趣激增，他们试图了解广泛的生物系统。在支持低温EM的研究基础设施方面进行了大量投资，最引人注目的是在全国各地建立了几个电子显微镜设施。在过去的几年里，制药公司和生物技术公司已经认识到低温EM对他们的发现管道的重要性，并开始在该领域进行投资。这一研究基础设施的一个关键组成部分是管理数据、处理显微图像和根据分子体积和/或原子结构解释数据的计算支持。电子冷冻显微镜合作计算项目(CCP-EM)是在2012-2016年间建立的，旨在提供这部分研究基础设施。拟议的项目旨在为低温显微镜社区提供持续支持。CCP-EM合作伙伴关系的主要产品之一是一套软件，用于处理在显微镜设施中收集的低温EM数据。该套件中的单个计算机程序由CCP-EM成员或合作者独立开发。CCP-EM的作用是将这些程序整理成一个单独的套件，通过该套件开发工作流程，并将该套件分发给执业科学家。如果做得好，这是一个双赢的安排，科学家可以在一个地方访问一套全面的软件，方法开发人员可以访问大量用户基础。然而，众所周知，如果不积极维护，软件很快就无法使用，确保套件中软件的寿命是CCP-EM核心团队的责任。我们还将扩大套件的范围。我们将改进验证所获得的结构性信息的工具，并便利将数据存放在国际档案中。我们将帮助推动公平的原则--更广泛的社区可以访问和使用来自低温EM实验的数据。我们将增加对亚断层图像平均的支持，这是一种获得原位分子结构信息的特殊技术。最后，我们会更多地使用机器学习，即可以从数据中学习的先进算法。所有这些进步都将与我们正在进行的用户培训计划紧密结合，并为个别方法开发人员提供支持。我们还将继续我们非常受欢迎的年度春季研讨会，该研讨会现在为300名研究人员提供了一个分享经验和发展CryoEM社区的论坛。

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.