DIALS / CCTBX: Serial crystallography computational methods aimed at biomolecular function

对人类健康至关重要的基本生化机制源于对蛋白质和核酸等生物大分子结构的了解。X射线结晶学已成为揭示其结构和功能的重要手段。该项目将开发使用系列X射线结晶学技术所需的计算方法。在第三代同步加速器光束线或X射线自由电子激光(XFEL)上进行的连续结晶学，正在成为一种利用晶体确定分子结构的方法，这些晶体用短的X射线脉冲探测一次，然后换成新的样品。这与传统的单晶实验不同，传统的单晶实验中，晶体在光束中旋转，以组装完整的数据集，但需要大晶体，再加上低温冷却，以减缓辐射损伤的影响。相比之下，连续结晶学是在极短的X射线脉冲下进行的，这种脉冲在辐射损伤发生之前探测结构，并在正常的生理温度下进行，在那里可以揭示所有可用的分子构象。软件工具包DIALS(高级光源的衍射积分)和CCTBX(计算晶体工具箱)从由布拉格斑点组成的衍射图中提取信息，对其进行分析最终得出分子结构。这一建议重新审查了存在了几十年的既定数据处理模式，并倾向于专门为序列结晶学定制的新模型，对以前没有得到适当处理的测量进行系统修正。这将提高精确度，甚至达到定位蛋白质中单个电子的水平。软件将与世界各地的几个XFEL光源合作部署，包括但不限于LCLS(斯坦福)、EuXFEL(德国)和SwissFEL(瑞士)，以及几个同步加速器源，如SSRL(斯坦福)、ESRF(法国)和钻石(英国)。代码将在一个开源的、面向社区的软件架构中分发，光束线科学家可以对该架构进行调整，以适应新的仪器设备，在一个预计将持续多年快速硬件进步的领域。

Basic biochemical mechanisms fundamental to human health arise from understanding the structure of large biological molecules, both proteins and nucleic acids. X-ray crystallography has been a key method for uncovering their structure and function. This project will develop computational methods needed to enable the use of serial X-ray crystallography techniques. Serial crystallography, performed at either third generation synchrotron beamlines or X-ray free-electron lasers (XFEL), is emerging as a way to determine molecular structure using crystals that are probed once with a short X-ray pulse and then exchanged for a new sample. This a departure from traditional single-crystal experiments where the crystal is rotated in the beam to assemble a full data set, but which require large crystals, coupled with cryocooling to slow down the effects of radiation damage. Serial crystallography, in contrast, is performed with an extremely short X-ray pulse, which probes the structure before radiation damage occurs, and at normal physiological temperatures, where the full range of available molecular conformations can be revealed. The software toolkits DIALS (Diffraction Integration for Advanced Light Sources) and CCTBX (Computational Crystallography Toolbox) extract information from the diffraction pattern consisting of Bragg spots, the analysis of which eventually leads to molecular structure. This proposal re-examines the established data processing patterns that have existed for many decades, and favors new models that are specifically customized for serial crystallography, making systematic corrections to the measurements that have not previously been treated properly. This will lead to improved accuracy, even to the level of locating a single electron in a protein. Software will be deployed in cooperation with several XFEL lightsources worldwide including but not limited to LCLS (Stanford), EuXFEL (Germany), and SwissFEL (Switzerland), and at several synchrotron sources such as SSRL (Stanford), ESRF (France), and Diamond (UK). Code will be distributed in an open source, community-oriented software architecture that can be adapted by beamline scientists to accommodate new instrumentation, in a field where rapid hardware advances are expected to continue for many years.