In a press conference Wednesday afternoon, Martin Karplus ’51, Richards professor of chemistry emeritus, spoke about his career trajectory and the research that earned him and two colleagues the 2013 Nobel Prize in chemistry, an award announced earlier in the day.
The Nobel committee cited Karplus, in conjunction with Michael Levitt of the Stanford University School of Medicine, and Arieh Warshel of the University of Southern California, “for the development of multiscale models for complex chemical systems.”
Their work bridges two physical models of understanding the world. Newtonian mechanics, with its key concepts of force, mass, and acceleration, has long been used to describe the motion of large entities—the arc of a ball tossed in the air, for instance, or an apple falling from a tree. Quantum mechanics, by contrast, describes motion at the level of single atoms and molecules, a minute and bizarre world in which a particle’s position is described by a probability, rather than certainty.
Quantum mechanics had always been applied in the domain of the minuscule, and classical physics in the realm of everyday objects, where the inherent randomness of any single particle would disappear once averaged among billions and trillions of other molecules. But Karplus and his colleagues were interested in large, biological molecules like proteins—too small for any microscope to see, but composed nonetheless of millions of atoms, far too many for any computer to simulate using the complex calculations of quantum mechanics. Newtonian mechanics was not sufficient either, because researchers were interested in molecules in motion—the changes in energy and molecular structure that occur when a protein recognizes its chemical target, for instance, or an enzyme catalyzes a reaction. “Motions are very important,” said Karplus. “Evolution has made the structure of proteins…so that they have a specific function…What the structures of the protein do is make the motions go…in a useful way.”
To model these larger molecules, Karplus and his colleagues (Warshel worked with Karplus at Harvard in the 1970s, and Levitt had been Warshel’s collaborator at Israel’s Weizmann Institute of Science) developed hybrid methods for combining the strengths of classical and quantum approaches. The researchers found that in a large molecule like a protein, some groups of atoms could be lumped together, simplifying the number of units in the overall structure, and they developed methods for predicting how these groups could be assigned. Their work helped researchers gain insight into the “action” part of biochemical reactions—how enzymes would change shape as they did their chemical job.
Their contributions to theoretical and computational chemistry have gone well beyond proteins. According to the press release from the Royal Swedish Academy of Sciences:
Today the computer is just as important a tool for chemists as the test tube. Simulations are so realistic that they predict the outcome of traditional experiments.
Karplus said the prize “consecrates” an entire field. “When we first began doing the type of work that was honored today, my chemistry colleagues thought it was a waste of time, because we couldn’t look at large molecules with methods that were hardly good enough to look at very small molecules,” he said. “My biology friends—not colleagues at that time—said that, well, even if we could do this, it wouldn’t be of any interest. In spite of this feeling,” he continued, “I thought that yes, we could do something, and we’ve been working on it now since the 1970s.”
Nearly half a century later, the methods he and his colleagues developed are widely used in both chemistry and structural biology, with applications that range from designing drugs to understanding how protein structures change in Alzheimer’s disease. Computational models built from the methods they helped pioneer enable researchers to predict how molecules will interact, allowing resource-intensive experiments to be more carefully designed. “I think that the Nobel Prize…in a way consecrates the field which has been contributed to by a large number of people, thousands of people nowadays, who are using calculations based on the methods that we began to develop in the 1970s,” Karoff told reporters.
Though his Nobel Prize was awarded in the field of chemistry, Karplus says he was always interested in biology. After his family left Austria in 1938, Karplus grew up in Newton, Massachusetts, where his older brother was given a chemistry set and the younger Martin a microscope. “Initially I was disappointed—no noise, no bad smells, although I soon produced the latter with the infusions I cultured from marshes, sidewalk drains, and other sources of microscopic life,” he wrote in an autobiographical essay titled “Spinach on the Ceiling: A Theoretical Chemist’s Return to Biology,” published in 2006 in the journal Annual Review of Biophysics and Biomolecular Structure (the piece’s title references macroscopic life forms of which the young Karplus was less fond).
The natural world soon won him over. Karplus spent his adolescent years steeped in ornithology, encouraged by mentors from the Harvard Museum of Comparative Zoology; at the age of 17, he traveled with researchers to Alaska to study migration patterns of golden plovers. It was as a freshman at Harvard College, studying under new chemistry professor Leonard Nash, that Karplus’s interests turned to chemistry. “I realized that what I really wanted to do was understand biological systems,” he said, “and the only way to do this was to do chemistry and physics.”
He went on to receive his doctorate at Caltech, studying with biochemist (and 1954 Nobel laureate in chemistry) Linus Pauling, eventually joining Harvard’s faculty in 1966. Karplus is the third living Nobel laureate in Harvard’s chemistry department, joining Emery professor of organic chemistry emeritus E.J. Corey (1990) and Baird professor of science emeritus Dudley Herschbach (1986; he brings to 47 the number of current and former Harvard faculty and alumni to receive a Nobel Prize for their work.
Karplus, who is also an avid photographer, said young scientists should be courageous and should not necessarily believe colleagues who say something is impossible. When asked about being a researcher, he emphasized the freedom to “try new things, even if you don’t know if they’ll work.”
“I do love my work,” he said in conclusion.
For more on Karplus, including an account of his Nobel-Prize-winning day, see coverage by the Harvard Gazette.
