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

University Of California-San Francisco, San Francisco CA

Investigators

Abstract

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.