Web Extras: Article

Teamwork Opens Evolutionary Window
By Erin Fults
Posted October 22, 2008

Two minds are often better than one, and the same goes for scientific techniques. Researchers who experiment in the lab are finding that computational methods can help them solve biological problems. Enzymologist Lizbeth Hedstrom knows this very well. She and computational biochemist Wei Yang joined forces to open a window into the mysteries of evolution.

Hedstrom, a professor at Brandeis University, has focused her attention on an enzyme with the tongue-twisting name of inosine monophosphate dehydrogenase. This enzyme, more easily called IMPDH, controls important cellular processes and is targeted by chemotherapy drugs and infectious parasites.

A model of the active site of IMPDH. The gray arrows (left) show the vestigial pathway, and the black arrow (right) shows the modern one.
Credit: Lizbeth Hedstrom
Click for larger image.

When Hedstrom and her team started to study the action of IMPDH, they became perplexed. The parts of the enzyme that they thought would be involved in triggering chemical reactions were not.

"We had thrown our whole experimental lunch bucket at the problem" says Hedstrom. "We had a mechanism that we thought was responsible, but [now] we were stuck."

Then she had the good fortune to meet Yang at Florida State University. He had developed computational tools that could simulate the mechanism of IMPDH. Initially skeptical of Yang’s approach, Hedstrom said she was surprised to find that his first calculations of her enzyme matched the experimental results perfectly.

And, each time they ran the computation and the experiment, the results matched "dead on," says Hedstrom. "It was quite phenomenal."

Plus, the combined approach finally revealed an explanation to the perplexing action of IMPDH. Typically, enzymes have a single pathway through which they deliver chemical agents needed to start cellular processes. But for IMPDH, the researchers found two active pathways, one of which was slower and less efficient. The researchers suspected that the slower pathway was "leftover" from IMPDH’s ancient ancestor enzyme and confirmed this hypothesis with evolutionary records.

Researchers could use this information to develop new drugs—particularly antiparasitic ones—that interact with the enzyme in therapeutic ways.

"By doing these computations, we got a window into evolution that we never would have had otherwise," says Hedstrom.

This "window" shows that the molecular processes and mechanisms that organisms, including humans, use today aren't necessarily the ones they used thousands of years ago. Consider the "evolution" of bicycles, says Hedstrom. "Bicycles are very different now than the way they started. Enzymes are like [any] technology. The final product you get after many, many years is different from the original one."

Even though she started out a skeptic, Hedstrom says this successful collaboration has made her "a big fan" of computation. She also believes that the use of computation could help other experimentalists who are at a "dead end" make exciting discoveries.

She says, "I think that what really makes the combination of computation and experimentation so powerful is that we can play [them] off of each other. It’s important to have that interchange of information."