Proteins In Motion: UMass Amherst Engineer Sarah Perry Aims to Develop the Next Generation of Molecular Imaging Technology

From developing cutting-edge pharmaceuticals with fewer side effects to getting new insight into our basic understanding of proteins, the field of structural biology is poised to take a new step forward at the University of Massachusetts Amherst thanks to a three-year, $936,000 grant awarded by the National Institutes of Health (NIH). Led by Sarah Perry, associate professor of chemical engineering at UMass, this grant will support the creation of a new device to enable the recording of proteins in action. 

“In making these platforms, we are looking to enable the next generation of structural biology experiments to allow scientists to learn more about drug binding, develop new therapeutic proteins or understand basic biology,” says Perry. “People have been able to make videos of protein structures before. The challenge is that doing the experiments is hard. We are developing technology to make it easier. In this sense, we are hoping to democratize it as a method, which could be revolutionary.”

Proteins play a pivotal role in every biological function, and structural biology explores how a protein’s function is defined by its shape and movement. Currently, scientists study protein shape by capturing still, three-dimensional pictures using X-ray crystallography—a well-established practice dating back to the 1960s. 

Traditional X-ray crystallography creates a still, 3-D image of a protein by shooting X-rays through a crystal of protein. The resulting diffraction can then, essentially, be worked backward to create an image. This is then repeated at various orientations of the crystal until the entire shape has been imaged to create a 3-D rendering. “If I took a picture of your face, I only know that about you—I know nothing about what the back of your head looks like,” Perry explains of how this the current X-ray crystallography process works. 

The challenge is that proteins are in motion. “Proteins are machines,” Perry says. “They move and they twist as they function. The technology that we’ve been using effectively takes that a still image of something very dynamic.” 

She compares it to viewing photos of a soccer game versus watching it on video. “Photos can tell you what happened, but you’re missing a lot of the detail—you might to get to see a player run up to the ball, and then the ball in the goal, but there is a lot that happens in between that doesn’t get captured.”

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With the grant, Perry aims to make a device that will enable X-ray crystallography to capture a 3-D rendering of a protein at many different time points, in much the same way that frames combine to create a movie. The device will be an array that can hold thousands of protein crystals so they can be analyzed efficiently, capturing the different angles and time points that can then be compiled into one, moving representation of a protein.

One application of this new tool will be in structure-based drug design. Drugs work by interacting with a protein to change its response. Side effects occur when that drug inadvertently impacts a different protein that is very similar. Historically, scientists have attempted to correct this by comparing the static structures of the two proteins. “However, there could be subtle differences in how the two proteins move,” she says. “If you could understand that and the molecular details of how those proteins function, you could imagine designing therapeutics that are very targeted and with greatly reduced side effects.”

Perry explains that previous attempts at time-resolved X-ray crystallography have focused on light-sensitive proteins because light is a fast enough trigger to function within this procedure. “But most proteins don’t care if you shine light on them,” she says. “They probably care if you give them the molecule that they bind to, or if you change the acid or base condition. They care about a chemical change, and that’s much harder to do.”

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With that in mind, Perry and her team are working to build a device that allows for control of other factors that are relevant to proteins, such as chemical reactions, electrical triggers or anerobic (oxygen-free) environments. 

“A lot of this work was really enabled by Sarthak Saha, who was a Ph.D. student in my lab and who is continuing as a postdoctoral researcher on this project,” she adds. “He came up with a lot of these ideas, he’s really the man on the ground. He has spent a ton of time with the people who are studying the specific proteins so that we understand their needs and can make the right device.”

At the completion of the grant, Perry hopes they will develop a series of devices that can be used for different types of experiments and that partnerships with collaborators at the national labs will help get their devices in the hands of the broader community.