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.

人类健康基本的基本生化机制是由了解蛋白质和核酸的大生物分子的结构而产生的。 X射线晶体学一直是发现其结构和功能的关键方法。该项目将开发用于实现串行X射线晶体学技术所需的计算方法。在第三代同步束线或X射线自由电子激光器（XFEL）上进行的连续晶体学已成为一种使用晶体来确定分子结构的一种方式，该晶体使用短的X射线脉冲探测一次，然后交换为新样品。这与传统的单晶实验背道而驰，在该实验中，将晶体旋转在光束中以组装一个完整的数据集，但需要大晶体，并与冷冻冷却型结合以减慢辐射损伤的影响。相比之下，串行晶体学以极短的X射线脉冲进行，该脉冲在辐射损伤发生之前探测结构，并且在正常的生理温度下，可以揭示出可用的分子构象的全部范围。软件工具包（用于高级光源的衍射集成）和CCTBX（计算晶体学工具箱）从由Bragg斑点组成的衍射模式中提取信息，这些衍射模式的分析最终导致分子结构。该提案重新检查了已经存在数十年的已建立的数据处理模式，并有利于专门定制用于串行晶体学的新模型，从而对以前未经适当处理的测量进行了系统的校正。这将提高精度，甚至达到蛋白质中的单个电子的水平。软件将与全球多个XFEL Lightsources合作部署，包括但不限于LCLS（Stanford），Euxfel（德国）和Swissfel（瑞士），以及在几个同步源，例如SSRL（Stanford），ESRF（France）和Diamond（UK）。代码将分布在开源的，面向社区的软件体系结构中，可以由光束线科学家改编以适应新的仪器，并在一个预计快速硬件进步持续多年的领域中。