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Laura L. Hunt
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UWM physicists assist international effort to speed protein imaging

Photo by Alan Magayne-Roshak

Abbas Ourmazd, UWM Distinguished Professor of Physics, led a team of UWM physicists in research that will help an international effort to make imaging certain proteins much easier.

Proteins are the essential ingredients of life. They carry out the instructions of genes. Without them, you can’t breathe, move, grow, heal or digest food. The root cause of many diseases is protein malfunction.

But scientists don’t know much about the structure of important classes of proteins because they are very difficult to image. And structure determines function.

A snapshot of a synthetic protein reconstructed from a simulation of the imaging method. The research was featured on the cover of Nature Physics in January.

Now, a team of physicists at the University of Wisconsin–Milwaukee (UWM), led by Professor Abbas Ourmazd, has made “seeing” proteins a whole lot easier. Their recently published work contributes to a new method of high-resolution imaging of proteins. It’s part of an international effort to condense a process that can take years to one that can be completed in days.

The UWM team, consisting of Ourmazd, Professor Dilano Saldin, and research scientists Russell Fung and Valentin Shneerson, has published research that was featured in two journals simultaneously in January – on the cover of Nature Physics and in Nature Methods. It also was highlighted as one of the most significant recent developments in condensed matter physics on the website of the American Physical Society.

The research has wide-ranging applications, from drug development to data mining.

In fact, the work of the international team that includes the UWM scientists is so significant they have been chosen to be among the first to test their ideas on the brand-new free electron laser that will be unveiled at the Stanford Linear Accelerator Center later this year.

Professor Dilano Saldin is co-investigator at UWM for the single protein imaging project.
(Photo by Thomas Story, ASU)

This next-generation free electron laser will produce X-rays that are brighter than any other source available. That intensity is needed to perform the imaging, called X-ray scattering.

While they have waited for the new laser, the UWM team has worked with scientists at Argonne National Laboratory to test their imaging method using deep ultraviolet light waves instead of X-rays.

Imaging without crystals
Until now, the best way to obtain information about a protein’s structure – what Ourmazd calls “its life story” – was to condense billions of proteins into a crystal and bombard the crystal with X-ray photons. The photons that bounce off the crystal reveal patterns that identify the protein structure.

Ourmazd compares the process to people sitting in a stadium: The crystal is the stadium, a set of ordered seats with one protein in each seat.

“Up until now, it has been necessary to get at least 100 million proteins to sit in this ‘stadium,’ shouting the same thing in unison,” he says. “A huge amplification was essential.”

The problem is, it can take up to a decade to crystallize new proteins because, like active kids, proteins don’t like to sit still in an ordered array of chairs.

So instead of crystallizing billions of proteins, it was suggested to shoot a trillion X-ray photons at just one protein. Before such a blast destroys it, the protein will diffract a mere 100 photons.

“This is like a protein whispering a random snippet of its life story in a noisy bar,” he says.

Ourmazd and his team have shown that by collecting many barely audible snippets from many single proteins – each scattering only 100 photons – they can reassemble the structure of the whole.

The UWM team developed an algorithm, a mathematical step-by-step procedure, for taking these groups of 100 photons, each scattered from an unknown structure at an unknown orientation, and piecing them together.

Research scientists and co-authors Valentin Shneerson (left) and Russell Fung. (Photo by Laura Hunt)

The algorithm is the magic recipe for putting all the snippets back together again – analyzing the data, he says. It is the reason the UWM team has had so many requests for collaboration from leading institutions in Sweden, Switzerland, Germany and the U.S.

Potential applications
The possibility of imaging hard-to-crystallize proteins has important implications for commercial use.

New drug discovery, in particular, is one field that would benefit from a better understanding of proteins. The majority of therapeutic drugs on the market target membrane proteins, which envelop the cell and keep it from falling apart.

“Cell membrane proteins control the flow of information and material into and out of cells,” says Ourmazd. “But they are notoriously difficult to crystallize.”

Since the new approach involves a series of instantaneous scatterings, the lessons learned here could be applied to creating medical imaging techniques that are tolerant of patient movement and minimize exposure to harmful radiation, he adds.

Also, with data growing daily by the petabyte, the project could enable sophisticated data mining. The method the scientists use is not far removed from the way people use search engines to gather bits of information on a single topic from the Web.

“Our approach is a powerful means of mining huge amounts of data to get information about specific, rare events,” says Ourmazd. Uses for such an approach, he suggests, include reconstructing randomly intercepted signals to uncover illicit activities, such as credit card fraud or even terrorist activities.

But for now, the team is focused on preparing for its time on the free electron laser. If the experiments are successful, says co-investigator Dilano Saldin, “a lot of people will be using this technique regardless of what molecule they are interested in studying.”