MRIConsortium: Collaborative Development of Sample Delivery Instrument for Femtosecond Diffraction Studies

斯坦福大学和加州大学旧金山分校（UCSF）获得了一项奖项，以开发一种用于结构生物学的多功能和优化的样品输送仪器，该仪器将最佳地利用SLAC国家加速器实验室（SLAC）的直线加速器相干光源（LCLS）的独特功能，LCLS是世界上第一台硬x射线自由电子激光器（XFEL）。它将为整个科学界提供一种新的资源来研究结构生物学中极具挑战性的问题。通过以原子或接近原子的分辨率对生物分子的结构和动力学进行成像，该仪器有望取得突破，从解开我们细胞如何沟通和发育的秘密，到药物发现和新疫苗的开发。该仪器的使用将通过同行评审，并向任何国内或国际结构生物学家开放，包括非博士学位的生物学家。和/或少数民族服务机构，谁有挑战性的大分子结构项目。一个仪器联盟将利用斯坦福大学、SLAC和UCSF提供的教育项目，提供与仪器开发和研究应用相关的实习机会。这包括一些面向本科生的项目，面向中学教师的项目和两个成熟的高中生实习项目。该联盟将为本科生、硕士和博士研究生、博士后以及对XFEL研究和飞秒衍射研究不熟悉的研究人员组织培训计划。通过让更广泛的受众接触到最先进的成像工具和LCLS XFEL提供的前沿研究机会，这些机会将吸引学生在职业生涯的早期阶段接触和参与科学、技术、工程和数学（STEM）领域。该仪器将安装在LCLS的大分子飞秒晶体学（MFX）光束线上，并与新兴的飞秒晶体学技术一起使用，飞秒晶体学技术发展迅速，对扩大我们对生物大分子结构和功能的认识有很大的希望。该仪器将通过扩展LCLS晶体学实验的实验选择，大大提高LCLS科学用户社区进行前沿结构生物学研究的能力。它将开启从具有挑战性的生物靶点的非常小、精致和辐射敏感的晶体中收集有用数据的可能性，包括膜蛋白和大的蛋白质复合物，有限供应的dna和rna，迄今为止尚未进行结构表征。XFEL光源的短脉冲长度和高峰值亮度可以减轻辐射损伤，并且可以从只有几微米或更小尺寸的晶体中收集数据，这是同步加速器光束线无法实现的实验。该仪器还将能够在同步加速器x射线源下快速进行辐射化学的敏感金属酶的高分辨率催化准确活性位点结构的测定。此外，用于这些实验的短（几十秒）x射线脉冲将提供比目前使用同步加速器更快的两到三个数量级的时域访问，以增强生化反应过程的时间分辨结构研究。这些实验能力是独一无二的，至少在美国是世界领先的。

An award is made to Stanford University and The University of California, San Francisco (UCSF) to develop a versatile and optimized sample delivery instrument for structural biology that will make optimal use of the unique capabilities at the Linac Coherent Light Source (LCLS), the world's first hard-X-ray Free Electron Laser (XFEL), at SLAC National Accelerator Laboratory (SLAC). It will deliver a new resource available to the entire science community to study extremely challenging problems in structural biology. By imaging the structure and dynamics of biological molecules, at or near atomic resolution, the instrument promises breakthroughs, from unlocking the secrets of how our cells communicate and develop, to drug discovery and development of new vaccines. Access to the instrument will be through peer-review and open to any structural biologists, nationally or internationally including those from non-Ph.D. and/or minority-serving institutions, who have challenging macromolecular structure projects. An instrument consortium will tap into educational programs offered at Stanford, SLAC and UCSF to provide internship opportunities related to the development and research applications of the instrument. This includes a number of programs geared towards undergraduates, programs for secondary school teachers and two well-established internship programs for high school students. The consortium will organize training programs for undergraduate students, M.S. and Ph.D. students, postdocs, and researchers who are new to XFEL research and femtosecond diffraction studies. By exposing a broader audience to the most state-of-the-art imaging tools and the cutting-edge research opportunities enabled by the LCLS XFEL, these opportunities will attract students into Science, Technology, Engineering, and Mathematics (STEM) fields through exposure and engagement at early stages of their careers. The instrument will be a user facility installed on the Macromolecular Femtosecond Crystallography (MFX) beamline at LCLS and used with the emerging technique of femtosecond crystallography, which has shown rapid development and great promise to expand our knowledge of the structure and function of biological macromolecules. The proposed instrument will substantially enhance the capability for the LCLS scientific user community to conduct leading-edge structural biology research by expanding the experimental options for crystallography experiments at LCLS. It will open up the possibility to collect useful data from very small, delicate and radiation sensitive crystals of challenging biological targets, including membrane proteins and large complexes of proteins, DNAs and RNAs in limited supply, that have thus far eluded structural characterization. The short pulse length and high peak brilliance of XFEL sources can mitigate radiation damage, and enable data collection from crystals of only a few microns or smaller in size, experiments not possible at synchrotron beamlines. The instrument will also enable the determination of catalytically accurate active-site structures to high resolution of sensitive metalloenzymes that quickly undergo radiation chemistry at synchrotron x-ray sources. Furthermore, the short (tens of fs) x-ray pulses used for these experiments will provide access to a time domain two-to-three orders of magnitude faster than currently accessible using synchrotrons, for enhanced time-resolved structural studies of biochemical reaction processes. These experimental capabilities are unique, at least in the U.S., and world leading.