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July 2005 Issue

Computational biologist Matthew Wortman, PhD
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It's All About Finding the Right Fit Faster

Published July 2005

Ask most biologists and chemists and they'll tell you drug discovery is all about the right fit.

"It really comes down to how one shape fits into another," says Matt Wortman, PhD, assistant professor and director of the Computational Biology Core facility at UC's Genome Research Institute (GRI). "Biology is basically about molecules bumping together. When molecules don't bump together correctly, you're in trouble."

If that sounds a lot like a puzzle to you, you're on your way to understanding how researchers go from sequences to solutions.

For most people, it's hard to fathom a drug does more than just enter your blood stream and magically make you feel better.

In reality, drugs diffuse throughout your body, looking for things to interact with. Those things are proteins which are created--or encoded--by your genes.

At the very basic level of science, before drugs can even be imagined, researchers need to know what proteins may be causing certain things to happen in the body. Once they have that information, they need to find out what they could use to make that protein function differently.

While this all seems difficult enough, it can get even tougher if the specific protein a researcher is studying has not been "crystallized"--meaning the structure has not been solved.

All of these scientific questions might go unanswered without technology. That's where computational biology comes in.

Computational biologists use high-powered computers to simulate interactions between proteins and compounds in three dimensions. They enter information into the computer about locations of molecules and types of chemical bonds. The computer then goes to work with mathematical equations to show what may be happening at the atomic level--at the same time producing pretty powerful images.

All this work, though much faster than the guessing game that could play out in a lab, can still take a computer days to figure out.

UC leaders recognized that if they were to be at the forefront of using science to develop better therapeutics, they would need to provide their researchers with the best equipment and expertise. Out of that realization came the Computational Biology Core at the GRI.

Basic biologists, says Dr. Wortman, have too many hoops to jump through and hurdles to clear to get the answers they need.

Providing them with computational technology allows researchers to ask more questions and solve problems that would normally require a lot of time and many high-throughput screenings.

"If there are people down that hall who can help with the technology end of things, scientists can go back to being scientists and get results they are looking for even quicker," says Dr. Wortman.

Dr. Wortman, a former molecular biologist, has always been interested in computers. While getting his PhD in neuroscience here at UC, he realized how important computation is to UC's drug discovery effort. Because he "spoke both languages," he was able to parlay his scientific expertise and love of computers into a career that links the two.

"We are sort of like technological interventionists," says Dr. Wortman. "A researcher brings us a protein or a sequence and says 'tell me what compounds might interact with this structure.' If the structure is known, we can produce a list of possible combinations and ask a medicinal chemist if the list makes sense.

"If there is no known structure, it's like a guessing game. We can predict the structure and guide the researcher from that point."

Although computational biology is used more and more, it's still very much in its infancy.

After completion of the sequencing of the human genome, the obvious next step was to learn more about protein structure. After all, it's the proteins--products of DNA--that make things happen in the body.

That quest for knowledge has in fact become sport-like.

"There are actually competitions for predicting protein structure," says Dr. Wortman.

"It's UC's goal to be a leader in the field of computational biology.

"Soon, more people will have the technology and skills to move bench science to a higher level," says Dr. Wortman. "We want to be building the framework for what will soon be the norm."

For more information about the Computational Biology Core, call Dr. Wortman at 558-4915.

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