Towards real-time XFEL data reduction with CCTBX

通过 CCTBX 实现实时 XFEL 数据缩减

• 批准号: 8704958
• 负责人: NICHOLAS K SAUTER
• 金额: $ 36.28万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704958
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Affect; Area; Biological; Communities; Computer software; Crystallography; Data; Data Collection; Data Set; Databases; Death Rate; Development; Diagnostic radiologic examination; Dimensions; Disease; Documentation; Drug Targeting; Educational workshop; Electrons; Feedback; Funding; HIV; HIV Protease Inhibitors; Head Start Program; Hour; Human body; Image; Investments; Knowledge; Laboratories; Lasers; Length; Letters; Libraries; Life; Light; Liquid substance; Maintenance; Marketing; Membrane Proteins; Methods; Modeling; Molecular; Molecular Structure; Output; Pharmaceutical Preparations; Pharmacologic Substance; Physiologic pulse; Process; Productivity; Proteins; Publications; Publishing; Pulse Rates; Research; Resources; Roentgen Rays; Running; Sampling; Savings; Schedule; Series; Solutions; Source; Structure; Surveys; Synchrotrons; System; Techniques; Technology; Time; Training; United States National Institutes of Health; Work; X ray diffraction analysis; X-Ray Crystallography; X-Ray Diffraction; attenuation; base; beamline; computerized data processing; cost; data reduction; design; drug development; drug discovery; experience; improved; indexing; instrument; interoperability; meetings; open source; pathogen; prevent; research facility; research study; structural biology; success; three dimensional structure; tool

DESCRIPTION (provided by applicant): The rapid development of HIV protease inhibitor drugs between 1989 and 1995 is an early success story of structural biology. Structural biology is concerned with three-dimensional structures of biological molecules. The structure of a molecule crucial in the infectious cycle of HIV was first published in 1989. Only six years later the first drugs targeting this molecule appeared on the market, leading to a dramatic decrease in the death rate from AIDS. In the 15 years since, drug development in general has become increasingly dependent on structural biology. Knowledge of the molecular structure of pathogens often suggests ways to disrupt their function. Compared to the traditional trial-and-error approach this can eliminate years of development time and cut many millions of dollars in development costs. - The predominant method for obtaining molecular structures is X-ray crystallography, which accounts for 87% of all biological structures known today. Long-term large-scale investments by NIH into research facilities of industrial dimensions have increased the number of structures solved per year to nearly 10,000. Unfortunately, certain highly important molecules are difficult to solve with current X-ray techniques. These are the membrane proteins, which are the targets of more than 60% of the drugs on the market. There is an estimated 5,500-7,700 membrane proteins in the human body, but fewer than a dozen structures of these are currently known. This is mainly because membrane proteins are notoriously difficult to crystallize. Without crystals of sufficient size conventional X-ray crystallography is impossible. - Very recently, a new major X-ray technology has emerged that promises to expand the reach to membrane proteins. The construction of the world's first hard X-ray Free Electron Laser (XFEL) was completed in 2009. The first publication of exploratory XFEL work on a membrane protein appeared in February 2011. An XFEL instrument can work with crystals of much smaller sizes than are needed for conventional experiments, sizes attainable even with membrane proteins. However, extracting structural information from an XFEL experiment currently takes many months. In about 28% of all cases, XFEL data processing is faced with ambiguities that prevent the extraction of high-quality results, compromising biological interpretation. For XFEL experiments to realize their full potential, the data processing times need to be decreased by at least two orders of magnitude and the ambiguities need to be resolved. - We have extensive experience developing data processing software for conventional X-ray experiments, with open-source implementations in the Computational Crystallography Toolbox (CCTBX). Building on our internationally recognized expertise and the large set of modular tools in CCTBX, we will implement real-time processing of XFEL data. This will include resolving ambiguities in the data if present, so that high-quality structural information will be within reach for all types of pharmaceutically relevant molecules.

描述（由申请人提供）：1989年至1995年之间HIV蛋白酶抑制剂药物的快速发展是结构生物学的早期成功故事。结构生物学与生物分子的三维结构有关。艾滋病毒感染周期中至关重要的分子的结构于1989年首次发表。仅六年后，针对该分子的第一批药物出现在市场上，导致艾滋病死亡率急剧下降。从那以后的15年中，药物开发通常越来越依赖结构生物学。对病原体分子结构的了解通常提出了破坏其功能的方法。与传统的反复试验相比，这可以消除多年的发展时间，并削减数百万美元的发展成本。 - 获得分子结构的主要方法是X射线晶体学，占当今已知的所有生物结构的87％。 NIH对工业维度研究设施进行的长期大规模投资将解决的结构数量增加到近10,000。不幸的是，使用当前的X射线技术难以解决某些非常重要的分子。这些是膜​​蛋白，它是市场上60％以上药物的靶标。人体中估计有5,500-7,700个膜蛋白，但目前已知的十几个结构少于十几个结构。这主要是因为众所周知，膜蛋白很难结晶。没有足够尺寸的晶体常规X射线晶体学是不可能的。 - 最近，出现了一种新的主​​要X射线技术，该技术有望将其扩展到膜蛋白。 2009年完成了世界上第一个硬X射线免费电子激光器（XFEL）的构建。探索性XFEL在膜蛋白上的首次出版物出版于2011年2月。XFEL仪器可以使用XFEL仪器使用的尺寸要小得多的晶体比常规实验所需的尺寸要小得多，尺寸可用于膜蛋白，即使是膜蛋白的尺寸。但是，目前从XFEL实验中提取结构信息需要数月。在大约28％的情况下，XFEL数据处理面临的歧义是防止提取高质量结果的歧义，损害了生物学解释。为了使XFEL实验具有全部潜力，需要将数据处理时间至少减少两个数量级，并且需要解决歧义。 - 我们有丰富的经验为常规X射线实验开发数据处理软件，并在计算晶体学工具箱（CCTBX）中具有开源实现。在我们国际认可的专业知识和CCTBX中大量模块化工具的基础上，我们将实施XFEL数据的实时处理。如果存在，这将包括解决数据中的歧义，以便所有类型的药物相关分子都可以触及高质量的结构信息。