Integrating 3D biological data on scales from molecules to cells

在最高层次的细节上，生物学变成了对分子机器的研究。这是一个真正复杂而迷人的世界；例如，分子机器产生力量，组装或分解其他分子，像通道一样工作，以及储存或运输能量。成熟的技术，如X射线结晶学、核磁共振(核磁共振)和电子显微镜(EM)能够在分子水平上可视化这些机器的三维(3D)结构，但这样做通常是以孤立和时间冻结的状态来研究它们为代价的。与日常机器一样，分子机器可能需要改变状态、改变形状或移动部件才能发挥其功能。就像工厂的装配线一样，许多生物过程涉及大量的分子机器，因此对孤立机器的冻结一瞥不足以理解“大画面”。新的显微技术的出现，如电子断层扫描(ET)、软X射线断层扫描(SXT)和三维扫描电子显微镜(3DSEM)，现在使人们能够在细胞的背景下可视化分子机械，甚至在3D中显示更大的结构，尽管还没有达到上述现有技术所提供的细节水平。现在的挑战是整合不同微观尺度的图像，以获得关于生物学3D微观宇宙的更广阔的视角。在这个项目中，我们将采取关键步骤，通过为EMDB档案开发增值服务，EMDB档案是由位于剑桥的欧洲蛋白质数据库(PDBe)及其国际合作伙伴管理的3DEM领域的最终档案。我们将通过以下方式来实现这一点：a)一个基于网络的可视化工具(体积浏览器)，它为用户提供从EMDB和PDB(生物大分子原子坐标模型的最终档案)档案中得出的细胞和分子级别的3D生物数据的一个容易获取的综合视图，这是在它们之间无缝导航和链接到其他相关生物信息学资源的手段；b)一个基于网络的工具，用于在EMDB的存档数据中添加生物注释，这对于实现(A)所述的整合至关重要；C)“原始”实验数据的试点图像档案，可用于开发新的EM方法以及检查在EM B中存档的3D结构的有效性。基于网络的卷浏览器和新的档案将使更广泛的生物医学科学界更容易获得各种3D结构信息。通过将细胞和分子结构数据联系起来而获得的背景和视角将提供仅从单个结构中无法获得的独特见解。此外，这些数据集通常包含比原始出版物中利用的信息多得多的信息。因此，卷浏览器将成为知识发现的重要工具。

At the highest level of detail biology becomes a study of molecular machines. This is a truly complex and fascinating world; for instance, molecular machines generate forces, assemble or disassemble other molecules, function like channels, and store or transport energy.Well established techniques such as X-ray crystallography, nuclear magnetic resonance spectroscopy (NMR) and electron microscopy (EM) are capable of visualizing the three-dimensional (3D) structures of these machines at the molecular level, but usually do so at the cost of studying them in isolation and in a state frozen in time. As with everyday machines, molecular machines may need to change state, change shape or move parts in order to perform their function. In analogy with an assembly line in a factory, many biological processes involve a multitude of molecular machines and a frozen glimpse of isolated machines is therefore insufficient for understanding the "big picture".The emergence of new microscopy techniques such electron tomography (ET), soft X-ray tomography (SXT) and 3D scanning electron microscopy (3DSEM) now makes it possible to visualise molecular machinery in the context of cells, and even larger structures in 3D, albeit not yet at the level of detail afforded by the established techniques mentioned above. The challenge now is to integrate imagery at different microscopic scales to gain a broader perspective on the 3D micro-cosmos of biology. In this project, we will take crucial steps in tackling this challenge by developing added-value services for the EMDB archive - the definitive archive for the 3DEM field managed by the Protein Data Bank in Europe (PDBe, located in Cambridge) and its international partners. We will achieve this by developing:a) A web-based visualisation tool (volume browser) that provides a user with an easily accessible integrated view of 3D biological data at the cellular and molecular scales derived from the EMDB and PDB (the definitive archive for atomic coordinate models of biological macromolecules) archives, the means to navigate seamlessly between them and to link to other relevant bioinformatics resources;b) A web-based tool for adding biological annotations to the archived data in EMDB, which is vital to achieve the integration described in (a);c) A pilot image archive for "raw" experimental data that could be used for developing new EM methodology as well as for checking the validity of 3D structures archived in EMDB.The web-based volume browser and the new archive will make a variety of 3D structural information vastly more accessible to the wider biomedical science community. The context and perspective gained by linking cellular and molecular structure data will provide unique insights that cannot be gained from the individual structures alone. Moreover, often these data sets contain much more information than what was exploited in the original publication. Therefore, the volume browser will become a vital instrument for knowledge discovery.