Towards real-time XFEL data reduction with CCTBX

通过 CCTBX 实现实时 XFEL 数据缩减

基本信息

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
项目类别：
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

项目摘要

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（申请人提供）：1989年至1995年间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。结构生物学关注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。仅六年后，第一种针对该分子的药物就出现在市场上，导致艾滋病死亡率急剧下降。此后的 15 年里，药物开发总体上越来越依赖于结构生物学。对病原体分子结构的了解通常会提出破坏其功能的方法。与传统的试错方法相比，这可以消除数年的开发时间并削减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，它占当今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当前的 X 射线技术来解析。这些就是膜蛋白，是市场上 60% 以上药物的靶标。人体内估计有 5,500-7,700 个膜蛋白，但目前已知的结构不到十几个。这主要是因为膜蛋白非常难以结晶。如果没有足够尺寸的晶体，传统的 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，有望扩大膜蛋白的范围。世界上第一台硬 X 射线自由电子激光器 (XFEL) 于 2009 年建成。关于膜蛋白的探索性 XFEL 工作的第一篇出版物于 2011 年 2 月发表。XFEL 仪器可以处理比实际尺寸小得多的晶体。传统实验所需的尺寸，甚至用膜蛋白也能达到。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，阻碍了高质量结果的提取，从而影响了生物学解释。为了让 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，并且需要解决歧义。 - 我们在开发用于传统 X 射线实验的数据处理软件方面拥有丰富的经验，并在计算晶体学工具箱 (CCTBX) 中实现了开源。凭借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存在的歧义（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。