Towards real-time XFEL data reduction with CCTBX

描述（由申请人提供）：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。结构生物学研究的是生物分子的三维结构。1989年首次发表了一种对HIV感染周期至关重要的分子结构。仅仅六年后，第一种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。从那以后的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，这种方法可以减少数年的开发时间，并节省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，占目前已知生物结构的87%。美国国立卫生研究院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，它们是市场上60%以上药物的靶标。据估计，人体内有5500 - 7700种膜蛋白，但目前已知的结构还不到12种。这主要是因为膜蛋白是出了名的难以结晶。没有足够大小的晶体，传统的x射线晶体学是不可能的。最近，一种新的主要x射线技术已经出现，有望扩大到膜蛋白的范围。世界上第一台硬x射线自由电子激光器（XFEL）于2009年建成。2011年2月，首次发表了关于膜蛋白的探索性XFEL工作。XFEL仪器可以处理比传统实验所需的小得多的晶体，即使是膜蛋白也可以达到这种尺寸。然而，从XFEL实验中提取结构信息目前需要几个月的时间。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，并且需要解决歧义。-我们在开发传统x射线实验数据处理软件方面有丰富的经验，在计算晶体学工具箱（CCTBX）中有开源实现。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歧义（如果存在），以便所有类型的药学相关分子都可以获得高质量的结构信息。

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.