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

DIALS / CCTBX：针对生物分子功能的串行晶体学计算方法

基本信息

批准号：
9886005
负责人：
NICHOLAS K SAUTER
金额：
$ 76.38万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-16 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886005
关键词：
Algorithms Architecture Area Back Biochemical Biological Cells Chemicals Code Communities Complex Computer software Computing Methodologies Coupled Crystallization Crystallography Custom Data Data Collection Data Set Diamond Electrons Enzymes France Generations Germany Grant Health Human Ions Light Link Maps Measurement Measures Metalloproteins Metals Methods Modeling Molecular Conformation Molecular Structure Motion Nucleic Acids Oxidation-Reduction Pattern Phase Physiologic pulse Physiological Problem Solving Proteins Publications Radiation induced damage Reaction Resolution Roentgen Rays Role Rotation Sampling Scientist Site Source Spatial Distribution Spottings Structure Switzerland Synchrotrons Techniques Technology Technology Transfer Temperature Testing Time Uncertainty Work X ray spectroscopy X-Ray Crystallography absorption beamline chemical reaction computerized data processing detector electric field electron density enzyme mechanism enzyme structure experience experimental study improved instrumentation metalloenzyme novel strategies open source preservation radiation effect simulation structural biology success temperature jump x-ray free-electron laser

项目摘要

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.

对人类健康至关重要的基本生化机制源于对大生物分子（蛋白质和核酸）结构的理解。 X射线晶体学是揭示其结构和功能的关键方法。该项目将开发使用串行 X 射线晶体学技术所需的计算方法。在第三代同步加速器光束线或 X 射线自由电子激光器 (XFEL) 上进行的串行晶体学正在成为一种利用晶体确定分子结构的方法，晶体用短 X 射线脉冲探测一次，然后更换为新的晶体。样本。这与传统的单晶实验不同，在传统的单晶实验中，晶体在光束中旋转以组装完整的数据集，但需要大型晶体，并结合低温冷却来减缓辐射损伤的影响。相比之下，串行晶体学是用极短的 X 射线脉冲进行的，它可以在辐射损伤发生之前和正常的生理温度下探测结构，可以揭示所有可用的分子构象。软件工具包 DIALS（高级光源衍射集成）和 CCTBX（计算晶体学工具箱）从由布拉格斑点组成的衍射图案中提取信息，对其进行分析最终得出分子结构。该提案重新审视了已存在数十年的既定数据处理模式，并倾向于专门为串行晶体学定制的新模型，对以前未正确处理的测量结果进行系统校正。这将提高准确性，甚至达到在蛋白质中定位单个电子的水平。软件将与全球多个 XFEL 光源合作部署，包括但不限于 LCLS（斯坦福）、EuXFEL（德国）和 SwissFEL（瑞士），以及多个同步加速器源，例如 SSRL（斯坦福）、ESRF（法国）和钻石（英国）。代码将分布在开源、面向社区的软件架构中，束线科学家可以对其进行调整，以适应新的仪器，在硬件快速发展的领域预计将持续多年。