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Cracking Molecular Structures with Bright Lights – and a Few Good Eggs

June 22, 2012 - 11:04am

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This rendering shows a lysozyme structural model against its X-ray diffraction pattern from SLAC’s Linac Coherent Light Source (LCLS), a powerful X-ray laser facility. Researchers have achieved high-resolution images of these simple biomolecules using advanced crystallography at LCLS. | Photo by Anton Barty/DESY

This rendering shows a lysozyme structural model against its X-ray diffraction pattern from SLAC’s Linac Coherent Light Source (LCLS), a powerful X-ray laser facility. Researchers have achieved high-resolution images of these simple biomolecules using advanced crystallography at LCLS. | Photo by Anton Barty/DESY

Which came first, the chicken or the egg?

Scientists still aren’t sure, but they could soon be cracking a few new protein structures thanks to a successful experimental coup by researchers at the SLAC National Accelerator Laboratory (SLAC).

SLAC scientists weren’t studying chickens. They were looking at a small protein found in egg whites called lysozyme. Proteins can serve as both a cell’s structural material and machinery, and lysozyme, which has also been studied extensively, serves as a cellular soldier – it fends off bacterial invaders.

So, why would SLAC scientists take another look at lysozyme – a protein they already know well? They did so to provide proof of concept of a powerful new technique called serial femtosecond crystallography. It’s a technique that was successfully tested at SLAC’s Linac Coherent Light Source (LCLS), the world’s most powerful X-ray free-electron laser.

The LCLS creates ultrafast, ultrabright X-ray pulses. These X-ray pulses are powerful and fast enough to make stop-action “pictures” of molecules in motion. That’s important since proteins are typically found in watery environments, which makes them, well, wiggly. But to determine their structures, and thereby better understand their functions, scientists typically try to make proteins sit still – such as by crystallizing them. However, large and important proteins such as cellular receptors – the target of many medicines – can be difficult to capture via crystallization.

SLAC’s new technique offers a way to get at the structures of large proteins without the painstaking process of attempting to grow them into large crystals. Instead, researchers can use tiny crystals no larger than a few micrometers, which are much easier to form. (A micrometer/micron is one-millionth of a meter, roughly the size of a large bacterium or a particle of dust.)

In this successful test, researchers were able to observe the 3-D structure of lysozyme at high resolution, based on X-ray diffraction of its microcrystals. The X-ray pulses using this technique were so powerful they destroyed the samples right after they hit, but the detector still picked up the diffracting signals from the samples before the onrushing X-ray pulse destroyed them. The resulting image of the structure was so detailed it showed the positions of some individual atoms. What’s more, the diffraction patterns showed no obvious signs of significant radiation damage, giving researchers confidence that the pulse didn’t destroy the samples before the diffraction, and the apparent positions of the atoms match the previous study.

Thanks to this ‘picture’ proof, the technique shows promise for helping researchers resolve the detailed structures of other important biological molecules. They might use it to learn more about the processes critical for photosynthesis, for instance, which could someday lead to the improved production of alternative energies. Or they could use it to discover more about proteins directly involved with diseases, which may lead to the development of new medicines.

The technique has been proven; the possibilities are just opening. And hopefully one day, after image has followed image and insight has followed insight, it will still be remembered that the lysozyme came first, imaged by a few good eggs from SLAC.

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