DIALS: New Computational Methods to Enable Challenging Crystallographic Experiments

 描述（由申请人提供）：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射线晶体学已成为揭示其结构和功能的关键方法。该项目将开发使用连续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上进行的连续晶体学正在成为一种使用晶体确定分子结构的方法，这些晶体用短X射线脉冲探测一次，然后交换新样品。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，连续晶体学是用极短的X射线脉冲进行的，它在辐射损伤发生之前探测结构，并且在正常的生理温度下，可以揭示所有可用的分子构象。程序DIALS（高级光源的衍射积分）将晶体衍射图案简化为列表 布拉格点强度，这是需要计算电子密度图导致原子模型。由于连续晶体学中的衍射图案是从静止的晶体而不是旋转的晶体中取样的，因此布拉格斑点强度的分析是完全不同的。首先，必须应用校正以将强度转换为来自单个旋转晶体的等效观测，然后必须合并来自潜在的数千个晶体的重复布拉格斑点测量以导出单个完整的数据集。该项目将探索在数据简化过程中所做的假设，并确定最佳的物理模型和算法，以获得最佳的合并数据。与此同时，DIALS将作为所有基于同步加速器的晶体学的通用数据简化包（用于串行和单晶方法）发布。DIALS是围绕一个开源的、面向社区的软件架构构建的，该架构可以由光束线科学家进行调整，以适应新的仪器，在这个领域，硬件的快速进步预计将持续多年。

 DESCRIPTION (provided by applicant): 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, 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 program DIALS (Diffraction Integration for Advanced Light Sources) reduces crystal diffraction patterns to a list of Bragg spot intensities, which are needed to compute the electron density map leading to an atomic model. Because the diffraction pattern in serial crystallography is sampled from still crystals rather than rotating ones, the analysis of Bragg spot intensities is entirely different. Frst, a correction must be applied to convert the intensity to the equivalent observation from a single rotating crystal, then duplicate Bragg spot measurements from potentially thousands of crystals must be merged to derive a single complete data set. This project will explore the assumptions made during this data reduction process, and identify optimal physical models and algorithms for deriving the best merged data. At the same time, DIALS will be released as a general data reduction package for all synchrotron-based crystallography (for both serial and single-crystal methods). DIALS is built around 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.