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)被授予开发一种用于结构生物学的通用和优化的样品输送仪器，该仪器将最佳利用SLAC国家加速器实验室(SLAC)的直线加速器相干光源(LCLS)的独特能力，该光源是世界上第一个硬X射线自由电子激光器(XFEL)。它将为整个科学界提供一个新的资源，用于研究结构生物学中极具挑战性的问题。通过以原子分辨率或接近原子分辨率成像生物分子的结构和动力学，该仪器有望实现突破，从解开我们细胞如何交流和发育的秘密，到药物发现和新疫苗的开发。该仪器的使用将通过同行审查，并向任何结构生物学家开放，包括来自具有挑战性大分子结构项目的非博士和/或少数群体服务机构的那些国内或国际结构生物学家。一个仪器联盟将利用斯坦福大学、SLAC和加州大学旧金山分校提供的教育项目，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，以及两个针对高中生的成熟的实习项目。该联盟将为本科生、硕士和博士生、博士后和新接触XFEL研究和飞秒衍射研究的研究人员组织培训计划。通过向更多的受众展示最先进的成像工具和LCLS XFEL带来的尖端研究机会，这些机会将通过在他们职业生涯的早期阶段接触和参与，吸引学生进入科学、技术、工程和数学(STEM)领域。该仪器将安装在LCLS的大分子飞秒结晶学(MFX)光束线上，并与新兴的飞秒结晶学技术一起使用，这一技术已经显示出快速发展和扩大我们对生物大分子结构和功能的知识的巨大希望。拟议的仪器将大大增强LCLS科学用户社区进行尖端结构生物学研究的能力，因为它扩大了LCLS晶体实验的实验选择。它将为从具有挑战性的生物目标的非常小、精细和辐射敏感的晶体中收集有用的数据开辟了可能性，包括膜蛋白和有限供应的蛋白质、DNA和RNA的大型复合体，这些迄今未能获得结构特征。XFEL光源的短脉冲长度和高峰值亮度可以减轻辐射损伤，并能够从尺寸仅为几微米或更小的晶体中收集数据，这些实验在同步加速器光束线上是不可能的。该仪器还将能够确定催化准确的活性中心结构，以获得高分辨率的敏感金属酶，这些金属酶在同步加速器X射线源上快速经历辐射化学。此外，用于这些实验的短(几十飞秒)X射线脉冲将提供比目前使用同步加速器可访问的时间域快两到三个数量级的时间域，用于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，至少在美国是独一无二的，而且是世界领先的。

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.