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Vol. LXVI, No. 3
January 31, 2014
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‘Father of Computational Enzymology’
Nobelist Warshel Visits NIH Ahead of Stockholm

On the front page...

2013 Nobel laureate Dr. Arieh Warshel
2013 Nobel laureate Dr. Arieh Warshel
How do complex chemical systems in the body work? We can answer this question, see simulations of the answer and even possibly visualize what sometimes goes awry—largely because of work done by 2013 Nobelist Dr. Arieh Warshel, who spent the last 45+ years disproving an idea he had as an undergrad.

“So the overall issue is, how do you model biological functions?” he said, showing an unpublished scientific manuscript he wrote in 1965. “I have been interested in enzymes since my undergraduate work in the Technion [Israel], where I looked at the effect of ionic strengths on the speed of chymotrypsin and concluded that electrostatic [force] is not important, which of course is wrong.”

Continued...

Chymotrypsin, an enzyme active in the pancreas, breaks down proteins in the body’s digestive system. Electrostatics describes the phenomena of electric charges that inhabit or are produced by just about everything. Warshel and colleagues have spent the last four decades uncovering the complicated functions of biological chemical systems at the molecular level and devising ways to make computers simulate those functions.

Offering a recent talk he described as “some part taken from the draft of the Nobel lecture, some part a little more hard-core,” Warshel was the final NIH-supported 2013 laureate scheduled to discuss his award-winning research here before accepting the prize in Stockholm in December.

A distinguished professor of chemistry at the University of Southern California, Warshel—along with Stanford’s Dr. Michael Levitt and Harvard’s Dr. Martin Karplus—won 2013’s Nobel in chemistry for developing multiscale models of complex chemical systems.

In the month following announcement of the awards, NIH’s lecture circuit was chock-full of grantee Nobelists: Dr. Randy Schekman, co-winner of the 2013 prize for medicine or physiology; Warshel’s good friend and collaborator Levitt; and Warshel all spoke at NIH within 3 weeks of each other.

Warshel (l), with NIH deputy director for intramural research Dr. Michael Gottesman, takes questions following the lecture.
Warshel (l), with NIH deputy director for intramural research Dr. Michael Gottesman, takes questions following the lecture.

Introducing the guest speaker, NIH deputy director for intramural research Dr. Michael Gottesman said Warshel “combines classical mechanics with quantum mechanics to model large systems. This is a combination of two approaches to understand complicated molecules at multiple levels. For this reason, [he] is considered the father of computational enzymology…His calculations have made contributions to a wide range of biological problems, including understanding mechanisms in vision, photosynthesis, ion channels, protein transport and protein folding.”

An NIH grantee since 1976, with support from NEI, NIGMS and NCI, Warshel was born in a kibbutz in Israel and spent 3½ years in the Israeli army, reaching the rank of captain in the reserve. After military service, he resumed his interest in chemistry, eventually studying Cartesian force fields, molecular mechanics, protein folding and other enzymatic reactions.

Throughout his early research career, however, Warshel said he kept returning to his original problem: needing a model to truly understand how enzymes work.

“When you try to study the function of proteins, there are problems that it’s very hard to understand—even when you have the biochemistry and the structure,” he explained. “You still don’t really know how it works...In my view, you could do it only with a computer.”

He likened the pursuit to trying to see how a clock works, by simply viewing its inner cogs and wheels.

“I would say biochemistry is the discovery of the clock, crystallography shows us the parts, single molecules determine how fast the motion [of the wheels] is, but we still need a model,” he said.

The 2013 Nobel laureate pauses for a photo op with Dr. Dale Lewis of NCI.

The 2013 Nobel laureate pauses for a photo op with Dr. Dale Lewis of NCI.

Photos: Bill Branson

Over the next several years, Warshel said he and colleagues “studied countless mutations and many different enzymatic reactions. We showed that we could reproduce the observed effect of mutations. More importantly, we showed that in any single case that we studied, at least 90 percent of the catalysis is due to electrostatic effect.”

Showing a self-deprecating sense of humor, Warshel liberally sprinkled his lecture—“Computer Simulations of Biological Functions”—with pop culture references. He used, for instance, an animation of the video game Pac-Man to illustrate chemical reactions versus regular reactions with and without enzymes. The soundtrack behind his animation of motor protein myosin’s walking motion was Gangnam Style, the chart-topping recording by South Korean artist Psy.

“I gave the lecture in Korea, you see,” Warshel quipped in explanation.

The computer modeling system that he developed has just as broad appeal: It has implications for every biological function in health and disease, from perhaps predicting HIV’s next move to calculating the path of drug resistance.

“There is nothing you cannot model relatively realistically, if you use a computer,” Warshel concluded.

The full lecture is archived online at http://videocast.nih.gov/summary.asp?Live=13368.


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