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Deep Insights from Thin Layers

March 13, 2014 - 4:08pm

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The Linac Coherent Light Source will create 3D images of single molecules using ultrafast pulses of very intense hard X-rays. | Image courtesy of SLAC.

The Linac Coherent Light Source will create 3D images of single molecules using ultrafast pulses of very intense hard X-rays. | Image courtesy of SLAC.

Proteins are critical to life; they’re the body’s essential cellular structures and machines.

But they’re also tough for scientists to capture images of, especially those that could become potential targets for new medicines. However, capturing images of -- and understanding -- those proteins may become a bit easier thanks to a team of researchers led by scientists at the Energy Department’s Pacific Northwest and Lawrence Livermore National Laboratories (PNNL and LLNL).

As published in the March issue of the International Union of Crystallography Journal, that team used the world’s most powerful X-ray laser at SLAC National Accelerator Laboratory (SLAC) to capture room-temperature images of proteins one super-thin layer at a time.

That’s significant for two reasons. First, about 25 percent of proteins simply don’t stack together easily. Proteins are "machines" in the sense that many of them speed (catalyze) critical chemical reactions, but they’re not the steely assemblies that might come to mind. Rather, they’re coiled and folded together from long strands of amino acids; many with loops and strands that ebb and flow in the cellular sea. In that sense, they’re closer to an octopus than a submarine.

However, stacking proteins is one of the best ways to "see" what they look like, and scientists want to do that, since the structure of a protein is a key to its function. To make that happen, scientists use a technique called crystallography, painstakingly searching for ways to turn nearly liquid proteins into harder, crystallized solids, which can then be examined by X-rays such as those at SLAC.

It’s even tougher to grow crystals from the complex proteins that are woven through cellular membranes. However, those proteins are of special interest to scientists, since many of them help cells communicate with their environments, and so could be the target of potential medicines.

The new technique, whose discovery was led by PNNL microscopist James Evans and LLNL physicist Matthais Frank, offers a way around that difficulty. Rather than spending years trying to grow protein crystals of sufficient size to be imaged by conventional techniques, the team of researchers used the power and precision of SLAC’s X-ray laser to image proteins just one layer thick. That makes it easier to capture images of the proteins. The team captured images of two proteins, streptavidin and bacteriorhodopsin, but there’s every expectation that the technique can be more widely applied.

Moreover, instead of freezing the samples -- as is often done in studying proteins -- the single layer technique can be done at room temperature. That’s significant since freezing can distort the shapes of proteins, suggesting structures that might not exist at room temperatures where proteins typically function. So the technique should allow scientists to get a much better sense of the true shapes of proteins – and therefore even more insight into what they do, and how to possibly affect what they do. That in turn could lead to new possibilities in a range of areas, from better biofuels to new medicines.

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