Acquisition of a Single Crystal X-ray Diffraction System for Macromolecular and Small Molecule Crytsallography

摘要 这项提议要求提供资金，用于购置一套X射线衍射系统，以满足 查尔斯号上一组由美国国立卫生研究院资助的调查员目前和未来的现场需求 波士顿大学的里弗河和医学院。拟议的文书将取代 已有11年历史的Bruker X8 Proteum-R衍射仪系统即将结束 使用寿命(2020年6月之后不提供部件/服务计划)。我们建议购买并安装 一种新仪器，具有可靠、低维护的X射线源和最先进的 探测器。布鲁克公司的I？S钻石铜源低功率运行，是风冷的，但X射线 其强度超过了现有旋转阳极X射线源的强度。提议的光子 III M28 CPAD探测器将大大提高对弱衍射样品的灵敏度，并 通过无快门图像采集功能，数据采集速度至少提高五倍。新的 仪器将更好地进行蛋白质筛选和大分子和蛋白质的数据收集 小分子晶体。基于更快的速度大大提高了小分子的性能 筛选确定目标样本的时间将通过更好的数据提高生产率 在信噪比方面的质量，以及提高数据收集的速度。快速数据收集 时间允许确定小分子的连接性和相对立体化学 其速度可与核磁共振相媲美。该系统将允许测定大分子 具有配体的结构和络合物，并提高小或弱衍射的数据质量 通过使用微聚焦源和大幅面探测器，这允许 提高了衍射光的空间分辨率。数据收集将通过利用 自动测角头寻找最佳晶体体积曝光，是一项不切实际的任务 在典型的测角器上使用粗略的手动测角扳手。ISX板材搬运 Stage将允许对机械敏感晶体进行现场筛选和数据收集，而无需 从结晶平板采集，并允许自动平板筛选，最大限度地提高用户的 大型筛选工作的工作效率。这些能力，将负担得起改进 以前无法使用的样本的吞吐量和数据收集将极大地支持和 加强NIH资助的五大六小用户项目。研究课题 包括对免疫缺陷中蛋白质-蛋白质相互作用的干预；定义细菌 生物合成途径；加速全身麻醉剂的发现；肌肉调节；氧化还原 调节；作为治疗药物的天然产品；可调有机半导体的合成；以及 合成多糖用于药物输送和恢复骨关节炎软骨的特性。

Abstract This proposal requests funds for the acquisition of a X-ray diffraction system that will meet the present and future on-site needs of a group of NIH-funded investigators located on the Charles River and Medical Campuses of Boston University. The proposed instrument will replace an eleven-year-old Bruker X8 Proteum-R diffractometer system which is reaching the end of its service life (no parts/service plan available after June 2020). We propose to purchase and install a new instrument featuring a reliable, low maintenance X-ray source and a state-of-the-art detector. Bruker’s IµS DIAMOND Cu source runs at low power and is air-cooled, yet the X-ray intensity surpasses the intensity of the existing rotating anode X-ray source. The proposed Photon III M28 CPAD detector will provide greatly improved sensitivity for weakly-diffracting samples and data collection at least five-fold faster via shutterless image acquisition capability. The new instrument will perform better for protein screening and data collection for macromolecular and small-molecule crystals. The vastly improved performance for small molecules based on faster screening time to identify target specimens will enable greater productivity through better data quality in terms of signal-to-noise, and enhanced speed of data collection. The fast data collection time allows determination of the connectivity and relative stereochemistry of small molecules with a speed rivaling that of NMR. The system will allow the determination of macromolecular structures and complexes with ligands and improve data quality of small or weakly diffracting crystals through use of the microfocus source and large-format detector, which allows for enhanced spatial resolution of the diffracted rays. Data collection will be optimized by utilizing the automated goniometer head to find the optimum crystal volume to expose, an impractical task using the coarse manual goniometer wrenches on the typical goniometer. The ISX plate-handling stage will allow in situ screening and data collection for mechanically sensitive crystals without harvesting from crystallization plates, and allow automated plate screening, maximizing users' work productivity for large screening jobs. These capabilities, which will afford improved throughput and data collection for samples that were previously unusable, will greatly support and enhance the NIH-funded projects of the five major and six minor users. The research topics include intervention in protein-protein interactions in immunodeficiencies; defining bacterial biosynthetic pathways; accelerating general anesthetic discovery; muscle regulation; redox regulation; natural products as therapeutics; synthesis of tunable organic semiconductors, and synthetic polysaccharides for drug delivery and to restore the properties of osteoarthritic cartilage.