Like tiny radio receivers, cells detect signals from the world around them. The “antennae” that collect the signals are proteins called receptors, and the signals are molecules called ligands. When a receptor couples with a ligand, the receptor’s three dimensional shape changes, and this change acts as a switch that relays the signal into the cell.
 Nagarajan Vaidehi investigates the structure of important proteins on the cell’s surface. (Photo by Paula Myers) |
Nagarajan Vaidehi, Ph.D., is developing highly advanced, computer-based methods to study how receptor proteins change their shape when they encounter ligands. The work may prove critical to the creation of new medications, because drugs act as ligands — and the technology is so promising it has garnered significant federal research funding.
Vaidehi, professor of immunology, and her research group are particularly interested in certain receptors on the cell’s surface called G-protein coupled receptors, or GPCRs. More than 50 percent of the drugs in today’s market target this type of receptor.
There are about 800 different G-protein coupled receptors, yet researchers have only determined the structure of four, and only one of those is human.
“GPCRs are very dynamic and constantly change shape in living cells,” said Vaidehi, “so using a static image of the receptor for drug design is misleading.”
Scientists have no way to systematically map how these proteins fold and change their shape, she said, but her team, which includes research scientist Spencer Hall, Ph.D., and postdoctoral fellow Supriyo Bhattacharya, Ph.D., is developing computational methods to change that. “It’s a very challenging problem, and we’re taking it head on,” Vaidehi said.
Fortunately, independent findings are starting to validate Vaidehi’s approach. Her team recently published results that predicted the shape of an active state of a G-protein coupled receptor called opsin. At almost the same time, another group crystallized opsin in a partially active state. The predicted results from Vaidehi’s group closely matched the actual active state of opsin.
“It was so gratifying to know that we’re moving in the right direction,” said Vaidehi. “We live for those moments when we make predictions and they come true.”
To advance their methods, Vaidehi and her team are adapting the calculations behind the design of a far different technology: robots that explore Mars.
Engineers at the National Aeronautics and Space Administration’s Jet Propulsion Laboratory developed advanced mathematical algorithms and software to design their Mars rover. They wanted the rover to be able to move about and bend and lift its robotic arm, so they used the software to “build” virtual rovers and test their ideas on computers before ever building a more expensive but real rover.
Vaidehi is using the same technique, but in reverse. While JPL engineers worked toward building their robots, Vaidehi’s team is starting with its own, already existing “machine” — the G-protein coupled receptor — and working backwards to study how it moves between active and inactive states. This technology could lead to more efficient development of new therapies.
The National Institute of General Medical Sciences, one of the National Institutes of Health, recently awarded Vaidehi a four-year, $1.2 million dollar grant to develop these algorithms and adapt them to the team’s studies.