New professor probes old mysteries of protein folding

By William J. Cromie

Gazette Staff

Eugene Shakhnovich, 39, is fascinated with the questions of how and why proteins fold themselves into intricate shapes. For the answers he has found so far, the Governing Boards, on Monday, approved his appointment as professor of chemistry and chemical biology, retroactive to Jan. 1.

"I think it's a wonderful thing for Harvard that Eugene was promoted," says David Nelson, Mallinckrodt Professor of Physics. "He comes from a great Russian tradition of theoretical science, and his expertise on protein folding is a superb asset for the University."

Every life on Earth depends on the activities of proteins, and these activities in turn depend on how proteins fold. When twisting and turning bring the right parts together, metabolism, motion, and senses operate as they should.

"When some proteins fold incorrectly, it leads to serious medical consequences, such as Alzheimer's disease," Shakhnovich notes. When a protein called Src folds one way, it is inactive; When it folds another way, it can either aid bone growth or cause the growth of cancer cells.

Dramatic Progress

In the 1980s, when he was a graduate student, then a postdoc, at Moscow State University and the Institute of Protein Research, solving the mystery of folding was thought to be impossible. But, Shakhnovich comments, "there has been dramatic progress in the 1990s.

"To some extent, this is due to dramatic advances in computer technology, but primarily it comes from an eclectic mixing of scientific cultures," he continues. "Physicists, physical chemists, and biochemists have developed a common language and are now cross-fertilizing each others' efforts."

Nelson gives Shakhnovich credit for the latter. "Eugene has helped bridge gaps between physicists and chemists and between chemists and biologists at Harvard and elsewhere," he says.

Shakhnovich made a name for himself in this field by elucidating the conditions under which folding can take place. Proteins are made from amino acids, simple combinations of nitrogen, hydrogen, oxygen and carbon. Shakhnovich determined that certain arrangements or sequences of these building blocks will cause an inactive linear chain to fold into an active three-dimensional structure.

His research also has produced deeper understanding of the motions and forces involved in the actual folding. Different parts of a molecule attract and repel each other. The resulting convolutions position active parts of proteins so they interact with other molecules. These interactions are responsible for most biochemical processes, including heartbeats, digestion, and breathing.

Shakhnovich is particularly interested in the role of protein folding in the origin of life. He envisions amino acids coming together randomly in some shallow primordial pool 3.5-4 billion years ago. After millions of years of trial and error, molecules arose that could reproduce themselves and could speed up that reproduction and other activities associated with life.

To understand how the first proteins folded, as well as all those that came later, Shakhnovich develops equations and computer models that attempt to reconcile all the chemical reactions and physical forces believed to participate in folding. This process generates predictions that laboratory scientists attempt to prove or disprove by experiments.

Because so many interactions take place on such a small scale in a very short time, "Eugene must simplify his models in order to make some kind of progress," Nelson points out. "It requires a great deal of insight and effort to make predictions that other scientists can test with experiments. Eugene is very good at that; he bridges the gap between theory and experiment the way he bridges gaps between physics, chemistry, and biology."

Growing Up

Shakhnovich grew up near Moscow. Both his parents were professors. His mother taught French language and literature; his father German language and literature.

"From age 9 or 10, I was fascinated with science," he recalls. "I wanted to know how nature works."

In high school, he participated in the physics Olympiad, winning the all-Soviet Union competition twice. At age 17, he won second place in the 1975 international Olympiad.

Shakhnovich chose Moscow University for his undergraduate and graduate work. There, he started working with polymers, large molecules made by repeatedly linking together smaller molecules. Synthetic polymers include plastics and artificial fibers, natural ones include proteins.

"I got bored with synthetic polymers," he recalls. "The most fascinating problems clearly involved proteins."

At the time, however, no paved academic avenues led where he wanted to go. Proteins belonged in the realm of biochemistry, not physics, and protein folding lay off the scholastic map.

"It was a challenge and a career risk," Shakhnovich says. "I decided to go for it, and I've never regretted that decision."

After finishing graduate school in 1984, Shakhnovich did postdoctoral research, then rose to the rank of senior scientist at the Protein Research Institute of the Soviet Union's Academy of Sciences. His accomplishments became known throughout the world.

In 1990, Martin Kaplus, Richards Professor of Chemistry, invited him to Harvard. Kaplus wanted to combine Shakhnovich's ideas about protein folding with computerized modeling techniques developed in this country.

Shakhnovich stayed with Karplus for a year, then Harvard offered him an assistant professorship in 1991. He rose to associate professor of chemistry in 1995.

In 1992, Shakhnovich won a coveted Packard Fellowship in Science and Engineering, which guaranteed him research support for five years.

Colleagues praise Shakhnovich for his first-rate intellect, as well as the enthusiasm and drive he brings to his research. He also draws accolades from both graduate and undergraduate students for being an effective teacher.

Shakhnovich teaches graduate courses in quantum mechanics, statistical mechanics, and advanced topics in molecular biophysics. His undergraduate subjects include physical chemistry and molecular biophysics.

Shakhnovich and his wife, Marsha, have two children, Boris, 17, and Irina, 13. Boris has applied for admission to Harvard and several other colleges. The family likes to walk, hike, bike, and keep in touch with their heritage through Russian literature, movies, and music.

"Boston is rich in Russian culture," Shakhnovich notes. "Another reason we enjoy living here."