Realizing New Horizons in X-ray Crystallography Data Processing

描述（由申请人提供）：本项目响应NIH/NIGMS计划公告PAR-10-073，高通量结构生物学技术开发。在过去的60年里，由X射线晶体学确定的大分子的原子结构导致了关键的生物学见解，并且仍然是当今学术和工业研究的主要焦点。X射线衍射实验主要在美国和国外的同步辐射设施中进行。实验的成功取决于收集大量衍射数据，通常来自大量晶体样品。如果衍射数据集可以立即处理，允许实时实验调整和/或检查替代晶体样品，则可以实现最佳结果。用于处理衍射图像的老化软件由于两个原因正在迅速过时。首先，衍射结果的多样性没有得到很好的模拟，其次，使用像素阵列技术的新一代X射线探测器将远远超过处理数据的能力。这些挑战将由在两个同步加速器设施（劳伦斯伯克利国家实验室的先进光源和斯坦福大学同步辐射实验室）工作的一组科学家在本提案中解决。一个新的软件系统，新视野，将被设计为高通量操作在同步加速器光束线，在那里它可以被纳入现有的软件环境，控制实验。晶体质量的快速测量将报告给实验者，以便进行协议调整。新系统将以现有的数据处理程序（如数据库管理系统）为基准，以确保遵守标准做法。通过在通用图形处理器（GPGPU）上实现软件，同时遵守OpenCL等标准以确保可移植性，将获得速度的数量级提升。GPU加速将允许实施基于小分子工作的上级模型，扩展数据处理精度和适用范围;特别是可以分析更广泛的含有晶格缺陷的晶体。将使用一个开放源模型，以确保世界各地的同步加速器设施可以利用和改造新视野号。 公共卫生相关性：PSI：生物学是NIH/NIGMS的一项倡议，将增加对蛋白质和DNA等大分子结构的理解。总体努力将通过检查致病蛋白质组中的数千种结构来探测感染性疾病，通过绘制蛋白质-药物相互作用来促进药物发现，并探测更大的复合物，包括整个病毒和大型分子工厂，如核糖体，伴侣蛋白和RNA聚合酶。该提案将为关键方法X射线晶体学建立关键的软件基础设施，从而以更高的通量和更自动化的方式解释分子衍射图案。

DESCRIPTION (provided by applicant): This project responds to NIH/NIGMS Program Announcement PAR-10-073, Technology Development for High-Throughput Structural Biology. The atomic structure of macromolecules as determined by X-ray crystallography has led to key biological insights in the last 60 years, and remains a prime focus of both academic and industrial research today. X-ray diffraction experiments are largely performed at synchrotron radiation facilities in the U.S. and abroad. The success of the experiment is dependent on the collection of large amounts of diffraction data, often from numerous crystalline samples. The best outcome is achieved if the diffraction datasets can be processed immediately, allowing real-time experimental adjustments and/or the examination of alternate crystal specimens. Aging software used to process the diffraction images is rapidly becoming obsolete for two reasons. First, the diversity of diffraction results is not well-modeled, and secondly, a new generation of X-ray detectors using pixel-array technology will far outpace the ability to process the data. These challenges will be addressed in this proposal by a team of scientists working at two synchrotron facilities (the Advanced Light Source at Lawrence Berkeley National Laboratory and the Stanford Synchrotron Radiation Laboratory). A new software system, New Horizons, will be designed for high-throughput operation at synchrotron beamlines, where it can be incorporated into existing software environments that control the experiment. Rapid measurements of crystal quality will be reported to the experimenter, so that protocol adjustments can be made. The new system will be benchmarked against existing data processing programs such as MOSFLM, to assure adherence to standard practice. Orders-of-magnitude advances in speed will be obtained by implementing the software on general purpose graphics processing units (GPGPUs), while at the same time adhering to standards such as OpenCL to assure portability. GPU acceleration will permit the implementation of superior models based on small-molecule work, extending both the data processing accuracy and range of applicability; in particular it will be possible to analyze a wider variety of crystals containing lattice defects. An open-source model will be used to assure that New Horizons can be utilized and adapted by synchrotron facilities worldwide. PUBLIC HEALTH RELEVANCE: PSI: Biology is an NIH/NIGMS initiative that will increase the understanding of the structure of macromolecules such as proteins and DNA. The overall effort will probe infectious diseases by examining thousands of structures in pathogenic proteomes, facilitate drug discovery by mapping out protein-drug interactions, and probe ever larger complexes including whole viruses and large molecular factories such as the ribosome, chaperonins, and RNA polymerase. This proposal will build critical software infrastructure for the key method, X-ray crystallography, allowing the interpretation of molecular diffraction patterns in a higher-throughput and more automated fashion.