X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded(1-3). It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source(4). We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes(5). More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (similar to 200 nm to 2 mm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes(6). This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.

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Femtosecond X-ray protein nanocrystallography

Researchers report sub-angstrom fundamental-wavelength lasing at the SPring-8 Angstrom Compact Free-Electron Laser in Japan. The output has a maximum power of more than 10 GW, a pulse duration of 10−14 s and a lasing wavelength of 0.634 A.

A compact X-ray free-electron laser emitting in the sub-ångström region

The field of laser-matter interaction traditionally deals with the response of atoms, molecules, and plasmas to an external light wave. However, the recent sustained technological progress is opening up the possibility of employing intense laser radiation to trigger or substantially influence physical processes beyond atomic-physics energy scales. Available optical laser intensities exceeding ${10}^{22}\text{ }\text{ }\mathrm{W}/{\mathrm{cm}}^{2}$ can push the fundamental light-electron interaction to the extreme limit where radiation-reaction effects dominate the electron dynamics, can shed light on the structure of the quantum vacuum, and can trigger the creation of particles such as electrons, muons, and pions and their corresponding antiparticles. Also, novel sources of intense coherent high-energy photons and laser-based particle colliders can pave the way to nuclear quantum optics and may even allow for the potential discovery of new particles beyond the standard model. These are the main topics of this article, which is devoted to a review of recent investigations on high-energy processes within the realm of relativistic quantum dynamics, quantum electrodynamics, and nuclear and particle physics, occurring in extremely intense laser fields.

Extremely high-intensity laser interactions with fundamental quantum systems

i»?The problem of phase retrieval, i.e., the recovery of a function given the magnitude of its Fourier transform, arises in various fields of science and engineering, including electron microscopy, crystallography, astronomy, and optical imaging. Exploring phase retrieval in optical settings, specifically when the light originates from a laser, is natural since optical detection devices [e.g., charge-coupled device (CCD) cameras, photosensitive films, and the human eye] cannot measure the phase of a light wave. This is because, generally, optical measurement devices that rely on converting photons to electrons (current) do not allow for direct recording of the phase: the electromagnetic field oscillates at rates of ~1015âHz, which no electronic measurement device can follow. Indeed, optical measurement/detection systems measure the photon flux, which is proportional to the magnitude squared of the field, not the phase. Consequently, measuring the phase of optical waves (electromagnetic fields oscillating at 1015âHz and higher) involves additional complexity, typically by requiring interference with another known field, in the process of holography.

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Phase Retrieval with Application to Optical Imaging: A contemporary overview

The start-up of the Linac Coherent Light Source (LCLS), the new femtosecond hard X-ray laser facility in Stanford, California, has brought high expectations of a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. Two papers in this issue of Nature present proof-of-concept experiments showing the LCLS in action. Chapman et al. tackle structure determination from nanocrystals of macromolecules that cannot be grown in large crystals. They obtain more than three million diffraction patterns from a stream of nanocrystals of the membrane protein photosystem I, and assemble a three-dimensional data set for this protein. Seibert et al. obtain images of a non-crystalline biological sample, mimivirus, by injecting a beam of cooled mimivirus particles into the X-ray beam. The start-up of the new femtosecond hard X-ray laser facility in Stanford, the Linac Coherent Light Source, has brought high expectations for a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. This new capability is tested for the problem of imaging a non-crystalline biological sample. Images of mimivirus are obtained, the largest known virus with a total diameter of about 0.75 micrometres, by injecting a beam of cooled mimivirus particles into the X-ray beam. The measurements indicate no damage during imaging and prove the concept of this imaging technique. X-ray lasers offer new capabilities in understanding the structure of biological systems, complex materials and matter under extreme conditions1,2,3,4. Very short and extremely bright, coherent X-ray pulses can be used to outrun key damage processes and obtain a single diffraction pattern from a large macromolecule, a virus or a cell before the sample explodes and turns into plasma1. The continuous diffraction pattern of non-crystalline objects permits oversampling and direct phase retrieval2. Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source5. Calculations indicate that the energy deposited into the virus by the pulse heated the particle to over 100,000 K after the pulse had left the sample. The reconstructed exit wavefront (image) yielded 32-nm full-period resolution in a single exposure and showed no measurable damage. The reconstruction indicates inhomogeneous arrangement of dense material inside the virion. We expect that significantly higher resolutions will be achieved in such experiments with shorter and brighter photon pulses focused to a smaller area. The resolution in such experiments can be further extended for samples available in multiple identical copies.

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Single mimivirus particles intercepted and imaged with an X-ray laser

The Linac Coherent Light Source free-electron laser has now achieved coherent X-ray generation down to a wavelength of 1.2 A and at a brightness that is nearly ten orders of magnitude higher than conventional synchrotrons. Researchers detail the first operation and beam characteristics of the system, which give hope for imaging at atomic spatial and temporal scales.

First lasing and operation of an ångstrom-wavelength free-electron laser

The LCLS hard X-ray Free Electron Laser at SLAC reported first lasing in April 2009. Since then two successful user runs have been completed at the two soft X-ray stations. The first hard X-ray station has started commissioning in July 2010. Beam diagnostics play an essential role for tuning the machine and delivering the requested beam properties to the users. An overview of the LCLS photon diagnostics will be presented including some selected commissioning results. Plans for future improvements and upgrades will be briefly discussed.

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H. Tompkins

Papers

First lasing and operation of an ångstrom-wavelength free-electron laser

Photon Beamlines and Diagnostics at LCLS