Abstract
X-ray free-electron lasers (XFELs) are revolutionary X-ray sources. Their time structure, providing X-ray pulses of a few tens of femtoseconds in duration; and their extreme peak brilliance, delivering approximately 1012 X-ray photons per pulse and facilitating sub-micrometre focusing, distinguish XFEL sources from synchrotron radiation. In this opinion piece, I argue that these properties of XFEL radiation will facilitate new discoveries in life science. I reason that time-resolved serial femtosecond crystallography and time-resolved wide angle X-ray scattering are promising areas of scientific investigation that will be advanced by XFEL capabilities, allowing new scientific questions to be addressed that are not accessible using established methods at storage ring facilities. These questions include visualizing ultrafast protein structural dynamics on the femtosecond to picosecond time-scale, as well as time-resolved diffraction studies of non-cyclic reactions. I argue that these emerging opportunities will stimulate a renaissance of interest in time-resolved structural biochemistry.
Highlights
Synchrotron radiation has had dramatic impact on the life sciences
I reason that time-resolved serial femtosecond crystallography and time-resolved wide angle X-ray scattering are promising areas of scientific investigation that will be advanced by X-ray free-electron lasers (XFELs) capabilities, allowing new scientific questions to be addressed that are not accessible using established methods at storage ring facilities
Further quantitative studies expanded and improved upon the physical model of the radiation damage process [28] and explored possible approaches for aligning and inverting X-ray scattering data from single particles [29,30,31]. The upshot of this body of theoretical work is that the major conclusions of our analysis [26] have stood the test of time: X-ray pulses of a few tens of femtoseconds or shorter will create a new opportunity for pushing back the traditional radiation damage limits of structural biology [32,33]; at the upper limits of the allowed X-ray fluence, it will be possible to collect interpretable X-ray scattering data from single large biological molecules such as viruses; and interpretable X-ray diffraction data will be recoverable from protein crystals only a few unit cells across. These considerations have featured among several early experiments at the Linac Coherent Light Source (LCLS) [14], the world’s first hard XFEL [12], and experimental data have demonstrated that the diffraction power of microcrystals falls off significantly as the X-ray pulse duration is extended beyond 70 fs [34]
Summary
Synchrotron radiation has had dramatic impact on the life sciences. The most visible application of synchrotron radiation is structural biology, which will soon pass the milestone of 100 000 structures deposited in the Protein Data Bank (www.pdb.org), of which approximately 90% are solved using synchrotron radiation. Radiation [14] have focused upon the development of serial femtosecond crystallography (SFX) as a high-resolution structural method [15,16,17,18,19,20,21]; the application of time-resolved approaches to SFX [22,23]; and the development of coherent X-ray imaging of single viruses [24] and cells [25] In this commentary, I discuss this recent progress and argue that XFEL radiation should be viewed as a complement to synchrotron radiation and single particle EM that will open up new scientific opportunities as well as accelerate the rate of progress in structural biology. I believe that one important avenue will be to probe the structural dynamics of biomolecules from atomic to cellular length scales on time-scales from femtoseconds to milliseconds
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