The free-electron X-ray laser (EXFEL) occupies a unique niche with its ability to obtain time-resolved atomic-resolution images of hydrated proteins under conditions of negligible radiation damage. This allows us to image molecular machines at work under near-physiological conditions, in the correct thermal bath, by using short pulses instead of cooling, to reduce radiation damage, while preserving heavy atoms in their correct oxidation state. In our second five years, the NSF-funded BioXFEL 7-campus Science and Technology Center in the USA will build on these early results, which I will review. <br/>   Femtosecond X-ray snapshots are recorded at 120 Hz before the onset of damage in both pump-probe and mixing-jet experiments which out-run radiation damage. Three time-resolved modes are in development - serial crystallography (SFX), single-particle studies (eg one virus per shot) and fast solution scattering (FSS). For SFX, where atomic resolution is possible using micron-sized crystals, the Schmidt group have led efforts to obtain "movies" of the cis-trans isomerisation reaction in photoactive yellow protein with 200 fs time resolution, the same process which occurs in the first event in human vision. I will also review experimental work aimed at snapshot imaging of enzyme-substrate reactions over much longer time-scales, using the mixing-jet technology we have developed. I'll summarize progress on the single-particle initiative, a large collaboration at the LCLS (with one particle per shot), where recent work has provided a 50 frame movie of a virus capsid expelling its genome and provided an energy landscape. A completely new approach to XFEL single particle imaging will be described, based on Intensity Interferometry of inner-shell X-ray fluorescence. I may also address the question of whether pulsed electron beams can also outrun radiation damage.<br/>   New XFELs have recently come on-line worldwide in Germany, South Korea and Switzerland, in addition to the machines in USA and Japan. I'll describe our campus compact XFEL under construction at Arizona State University, which uses a laser as a wiggler.

Imaging protein dynamics with an X-ray laser

256th National Meeting (2018)

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