IU scientist, collaborators receive $1 million international research award to study enzymes

An Indiana University professor and others have been awarded $1 million from the Human Frontier Science Program to pursue international research on how enzymes work inside living cells.

The IU recipient is Trevor Douglas, a professor in the IU College of Arts and Sciences' Department of Chemistry. Other recipients are Pedro J. de Pablo, a professor of physics at the Autonomous University of Madrid in Spain, and Claudia Vickers, an associate professor of chemical biology at The University of Queensland in Australia.

The Human Frontiers Science Program provides support for scientists to collaborate across borders and disciplines on problems in the life sciences. Together, the researchers will use their expertise in chemistry, physics and biology to study enzymes that are a part of a biological process called the "isoprenoid pathway."

Isoprenoids are carbon-based molecules that play a variety of important biological functions in plants, among other organisms. They can also be used in manufacturing processes to create products such as fragrances and biofuels.

Specifically, the researchers will study these enzymes by trapping them inside a hollow protein shell structure, called a capsid, that is derived from viruses. This protects the enzymes from the environment and gives researchers the ability to study their behavior without interference from other large molecules, a common problem when studying molecules in living organisms.

"People have tried for a long time to use these enzymes industrially with limited success," said Douglas. "The goal here is to take some of the key enzymes in the pathway and trap them inside the virus particle which will protect what's inside. Putting these enzymes inside the capsids will likely make them work better and for much longer."

Douglas' work has previously used similar techniques to advance research on chemical reactions with potential applications to hydrogen biofuel production.

The team will also study how enzymes in the isoprenoid pathway behave in response to "molecular crowding" by placing multiple enzymes inside a single capsid. Douglas said this work has the potential to produce insights with "significant industrial applications."

The image caption followsView print quality image
This illustration depicts an hydrogen-producing enzyme trapped inside a virus capsid. A similar method will be used to study enzymes in the isoprenoid pathway under the grant from the Human Frontiers Science Program. Photo courtesy of Ella Marushchenko

"Although we're mostly interested in basic research questions, we chose these enzymes specifically because we want to conduct work on systems that are relevant -- that affect people's lives," he added. "We don't want to produce new knowledge that's going to be forgotten after it's published."

The first step in the collaboration took place last fall at the Autonomous University of Madrid, where Douglas and colleagues at de Pablo's lab set up experiments to analyze how individual enzyme particles inside capsids behave in response to various changes in their environment.

This work uses a specialized device at the lab called an atomic force microscope, which uses a tiny pointed tip to scan across the surface and map the shape and other features of the virus -- as well as apply pressure to mechanically distort the structure of the virus particle.

After refining their analysis technique with "practice" enzymes, the researchers will then incorporate into their experiments the enzymes that make up the isoprenoid pathway. The enzymes will come from Vickers' lab in Australia.

Douglas said the goal is to fully utilize the expertise of everyone in the partnership, particularly graduate students.

"This award will provide great experiences to our graduate students," he said. "We're looking forward to a great exchange of personnel, with students traveling between our three institutions to learn each other's methodologies and gain experience abroad."

The merger of three disparate areas of expertise -- biology, physics and chemistry -- to produce new knowledge is a unique challenge with unique rewards, he added.

"We're looking forward to pushing forward on some questions that we haven't been able to answer using other methods," said Douglas. "I think this collaborative approach is going to give us a whole different set of insights."