A new world-class tool for examining the structures of complex molecules was added last month to the suite of technologies available at the Stanford Synchotron Radiation Lab (SSRL) facility at the Stanford Linear Accelerator Center (SLAC). The new “molecular observatory” — also known as an x-ray beamline — was funded by the California Institute of Technology (CalTech) with a grant from the Gordon and Betty Moore Foundation.

Scientists hope that the automated new x-ray beamline will enable researchers around the globe to study the structures of larger molecules in smaller quantities — breaking the field of structural biology wide open.

“This is the most advanced instrument that we have,” said SSRL scientist Keith Hodgson. “You can really push at the frontiers of biocomplexity.”

The new beamline will be used in a technique called x-ray crystallography, which scientists use to take pictures of the shapes of large molecules like enzymes and other proteins. In crystallography, a beam of x-rays is shot through a crystalline array of molecules that then bend the radiation in characteristic patterns. These patterns are not exact images of the molecules, but scientists can use them to calculate molecular structures.

“X-rays are the most used and powerful method to determine the structure of macromolecules,” said SSRL Director Joachim Stohr. “We have to build a crystal out of individual proteins. We have thousands of millions of these proteins all lined up. When we shoot our x-ray through we get a diffraction pattern, and from that pattern we can deduce the structure of an individual protein that sits within the crystal.”

“You can think of [crystallography] like a microscope,” Structural Biology Prof. Bill Weis said. “You shine light at something and you observe its image. The problem is we have no x-ray lens, so we have computational patterns that we use to reconstruct the image.”

Weis is one of a number of scientists around the world who will be able to use the new facility. The beamline will enable him to determine the structures of molecules that are not normally soluble in water — proteins bound up in the membranes of cells. These molecules are often more difficult to crystallize: Out of the 42,626 proteins with known structures, less than five percent are membrane-bound.

“In my own work, we’re studying another class of membrane proteins,” Weis said. “You have to dissolve them in detergent. What we typically have are very thin crystals — samples that are 5 to 10 micrometers on a side.”

At that size, he explained, the samples would be too small for even a regular synchrotron beamline to analyze. Previous SSRL facilities could determine the structure of molecules in 50 to 100 micrometer crystalline samples, 10 times the size of the largest crystals Weis could produce.

“It may not sound like a big difference,” Weis said, “but practically it turns out to be a very large difference in terms of what you actually study.”

Use of the technology will not be restricted to scientists at SLAC. CalTech is guaranteed priority access to 40 percent of the beam time, and the other 60 percent will be allotted following a peer-reviewed research proposal process.

“The way that this was funded, all of the money came from CalTech,” Hodgson explained. “Stanford doesn’t gain any guaranteed access.”

He added: “The beam time is made available on the basis of quality of science.”

Because SSRL is funded by the U.S. Department of Energy, scientists not working for private companies can use the facility for free. If scientists from private companies wish to use the new facility, the charge is about $2,000 for eight hours — the cost the Department of Energy pays to operate the facility for that amount of time.

Prior to the development of this facility, the best available x-ray beamlines of this kind were located in Europe, according to Hodgson. Now, scientists from across the United States will have access to the technology, thanks to automated remote access built into the facility.

“Using macromolecular crystallography, one can gain access to the type of information that is personified in the Nobel Prize work of Roger Kornberg,” Hodgson said. “This brings that capability even more readily to the people at SLAC and Stanford.”