Molecule and Market Studies Capture Nobel Laurels


You've seen the models—molecules represented as balls connected by sticks, often pared down to a few lines on paper. Useful as they are to chemists, they leave out something essential: motion, the intricate dance of electrons and atomic nuclei breaking and fusing bonds as they undergo reactions. That dance is the heart of chemistry. Last week's Nobel Prize in chemistry was awarded to three U.S.-based scientists for developing computer models that reveal how proteins and other compounds perform it.

All three of this year's chemistry laureates are naturalized U.S. citizens. Martin Karplus of Harvard University and the University of Strasbourg in France was born in 1930 in Vienna and moved to the United States just before the outbreak of World War II. Michael Levitt of Stanford University's School of Medicine in Palo Alto, California, was born in Pretoria in 1947, and today is a British, U.S., and Israeli citizen. And Arieh Warshel of the University of Southern California in Los Angeles was born in 1940 in Kibbutz Sde-Nahum, Israel, and still holds Israeli citizenship.

More than 40 years ago, the three pioneered new tools for fusing two disparate world views among chemists working to simulate molecules. One of them, grounded in classical Newtonian physics, treated molecules as collections of atomic balls connected by springlike bonds. Because this approach was mathematically tractable for large numbers of atoms, it enabled researchers to simulate proteins and other large molecules. In 1969, Levitt and Warshel, then both at the Weizmann Institute of Science in Rehovot, Israel, designed a ball-and-spring computer model that could track how proteins and other large biomolecules oscillate and twist. But it couldn't calculate the changes in energy involved when chemicals react and form new molecules.

Meanwhile, at Harvard, Karplus was deeply enmeshed in the second approach to simulation, called quantum chemistry. It was far better at simulating the motion of the electrons and atomic nuclei involved in reactions. But it was so computationally demanding that it was useful only in solving the behavior of small molecules.

Trying to bring the quantum and classical worldviews together "was a fairly natural progression," Levitt told reporters last week. In 1970, Warshel visited Karplus's lab and brought his classical program with him. The two soon constructed a program that melded their approaches, treating mobile, covalent bond–forming electrons (pi electrons) with a quantum chemical approach and less mobile ones (sigma electrons) as well as atomic nuclei classically. They used their hybrid approach to calculate the behavior of simple organic molecules.

In 1976, Warshel and Levitt followed up with a more general approach and showed that it worked for simulating the behavior of the protein lysozyme. They used quantum chemistry to handle lysozyme's reactive core but a classical approach to deal with more distant parts of the molecule. The strategy—akin to devoting extra pixels to the focal point of an image to improve its resolution—remains at the heart of computational chemistry. "The prize recognizes developments that started over 40 years ago that still reverberate today through much of chemistry and biology," says Klaus Schulten, a molecular modeling expert at the University of Illinois, Urbana-Champaign.

Today, those reverberations include hybrid "multiscale models" capable of simulating more than 4 million atoms, which are revealing the complexities of processes as diverse as the translation of genes into proteins and the photosynthetic conversion of sunlight into chemical fuel. Thousands of researchers are hard at work in the field. Still, Schulten says, the Nobel Committee chose well: "If you had to single somebody out, I think there's a good case to be made that these three were the right choice."

Even so, Warshel says he was wary when he reached for the ringing phone at 2 a.m. on 9 October: "I checked to see if they talked in a Swedish accent just to be sure."