Integrating 3D biological data on scales from molecules to cells

在细节的最高层次上，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，组装或拆卸其他分子，像通道一样起作用，储存或运输能量。诸如x射线晶体学、核磁共振波谱学（NMR）和电子显微镜（EM）等成熟的技术能够在分子水平上可视化这些机器的三维（3D）结构，但通常这样做的代价是在隔离和时间冻结状态下研究它们。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以执行其功能。与工厂的装配线类似，许多生物过程涉及大量的分子机器，因此，对孤立机器的冰冻一瞥不足以理解“大局”。新的显微镜技术的出现，如电子断层扫描（ET）、软x射线断层扫描（SXT）和3D扫描电子显微镜（3DSEM），现在使得在细胞背景下可视化分子机制，甚至更大的3D结构成为可能，尽管还没有达到上述既定技术所提供的细节水平。现在的挑战是在不同的微观尺度上整合图像，以获得对生物的三维微观世界的更广阔的视角。在这个项目中，我们将采取关键步骤，通过为EMDB档案开发增值服务来应对这一挑战。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。我们将通过开发：a)基于网络的可视化工具（体积浏览器），为用户提供易于访问的细胞和分子尺度的3D生物数据集成视图，这些数据来自EMDB和PDB（生物大分子原子坐标模型的最终档案）档案，可以在它们之间无缝导航并链接到其他相关的生物信息学资源；b)一个基于web的工具，用于向EMDB中的存档数据添加生物注释，这对于实现(A)中描述的集成至关重要；c)用于“原始”实验数据的试点图像存档，可用于开发新的EM方法以及检查存档在EMDB中的3D结构的有效性。基于网络的体积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。通过连接细胞和分子结构数据获得的背景和视角将提供单独从单个结构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所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.