Towards real-time XFEL data reduction with CCTBX

通过 CCTBX 实现实时 XFEL 数据缩减

• 批准号: 8551674
• 负责人: NICHOLAS K SAUTER
• 金额: $ 35.01万
• 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/8551674
• 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年期间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。结构生物学研究生物分子的三维结构。在HIV感染周期中至关重要的一种分子的结构于1989年首次发表。仅仅六年后，第一批针对这种分子的药物出现在市场上，导致艾滋病死亡率急剧下降。在此后的15年里，药物开发总体上越来越依赖于结构生物学。了解病原体的分子结构通常会提供破坏其功能的方法。与传统的试错法相比，这可以减少数年的开发时间，并减少数百万美元的开发成本。- 获得分子结构的主要方法是X射线晶体学，它占今天已知的所有生物结构的87%。NIH对工业规模研究设施的长期大规模投资使每年解决的结构数量增加到近10，000个。不幸的是，某些非常重要的分子很难用目前的X射线技术来解决。这些是膜蛋白，这是市场上超过60%的药物的目标。据估计，人体内有5500 - 7700种膜蛋白，但目前已知的结构不到12种。这主要是因为膜蛋白是出了名的难以结晶。没有足够大的晶体，常规的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，有望扩大对膜蛋白的研究范围。世界上第一台硬X射线自由电子激光器（XFEL）的建造于2009年完成。2011年2月首次发表了XFEL膜蛋白的探索性工作。XFEL仪器可以处理比传统实验所需小得多的晶体，甚至可以用膜蛋白来实现。然而，从XFEL实验中提取结构信息目前需要数月时间。在大约28%的情况下，XFEL数据处理面临着模糊性，这阻碍了高质量结果的提取，影响了生物学解释。为了使XFEL实验充分发挥其潜力，数据处理时间需要减少至少两个数量级，并且需要解决模糊性。- 我们在开发传统X射线实验数据处理软件方面拥有丰富的经验，并在计算晶体学实验室（CCTBX）中实现了开源。基于我们国际公认的专业知识和CCTBX中的大量模块化工具，我们将实现XFEL数据的实时处理。这将包括解决数据中的模糊性（如果存在），以便所有类型的药物相关分子都能获得高质量的结构信息。