Chemists Martin Karplus and Arieh Warshel and biologist Michael Levitt each played an integral role in developing computer-based methods for studying complex chemical systems and reactions – in essence moving chemistry out of the lab and into the computer. This month they were each honored by the Royal Swedish Academy of Science with the 2013 Nobel Prize in chemistry.
“Leonard Nash was a marvelous lecturer,” says Martin Karplus, the Theodore William Richards Professor Emeritus of Chemistry at Harvard University, in Cambridge Massachusetts, US, speaking fondly of the inspirational 1947 freshman chemistry class at Harvard. “Six or seven of us would regularly stay after class and talk about all of the sciences from every angle. We talked about our ideas - it was a really special time.”
Karplus earned his PhD while working with two-time Nobel laureate Linus Pauling and then taught at the University of Illinois, Columbia University, and the University of Paris before returning to Harvard to teach in 1966. Eric Heller, the Abbott and James Lawrence Professor of Chemistry and a longtime friend, remembers a winter day when Karplus trudged in to work, forgetting his notes. What followed was a brilliant ad hoc lecture, Heller says, which made him think Karplus was destined for the Nobel Prize. “I have no recollection of the lecture,” says Karplus, “but it must have made an impression.”
Karplus was interested in understanding exactly how chemical reactions worked – grasping the dynamics involved and understanding individual atoms in the most critical area of a molecule. Reaction speeds made lab study impossible, so he turned to quantum physics. “It turned out that this quasi-classical method we invented and used gave us excellent results for the hydrogen atom plus a hydrogen molecule reaction – but, if you wanted to do something more complicated like a macromolecule, the quantum mechanical calculation was very complicated.”
Arieh Warshel, Distinguished Professor of Chemistry at the University of Southern California Dornsife College of Letters, Arts and Sciences, in Los Angeles, US, left the Weizmann Institute in Israel in 1972 to join Karplus’ lab at Harvard as a postdoctoral fellow. Prior to joining Karplus, Warshel worked in the lab of Shneior Lifson at Weizmann, where he developed models much like the ones Karplus was working on – but, instead of quantum mechanics, he used classical mechanics.
Karplus and Warshel developed a strategy of using quantum mechanics to simulate parts of a molecule that need high accuracy, and then classical mechanics for everything else. This combination of approaches – the blending of the two branches of physics – laid the foundation for models that are crucial for most of today’s advances in biochemistry.
Warshel reported the first molecular dynamics simulation of a biological process in a 1976 study.“In short, we developed a way which requires computers to look, to take the structure of the protein and then to eventually understand how exactly it does what it does – methods that allow us to see how proteins actually work,” Warshel says. Before leaving Shneior Lifson’s lab at Weizmann, Wershel worked closely with Michael Levitt, who now holds the Robert W. and Vivian K. Cahill Professorship in Cancer Research at Stanford's School of Medicine in California, US.
During his PhD, Levitt had used the standard model to look at the enzyme reaction of lysosome - the crystal structure of which had been solved in 1964 by David Phillips. “His paper was published in Scientific American,” Levitt says, “which was interesting because in those days Scientific American was the only journal that actually allowed one color picture, and that was on the cover. So that was the place for many big scientific discoveries.”
Phillips proposed that the enzyme works by taking its substrate and physically straining it or breaking it, but the calculations Levitt did during his PhD showed that proteins were too soft for this to work. It would have been like trying to break something over a big fluffy cushion – so the question became one of how to break the bond. “Wershel was the driving force once quantum mechanics were involved,” Levitt says. However, if you ask Wershel or Karplus, they will tell you that Lifson should be credited with devising how to treat the potentials for complex molecules in a way that is generalized for large systems.
No matter how far you go back, one thing is certain: The announcement of the 2013 Nobel Prize in chemistry – awarded jointly to Karplus, Wershel, and Levitt – solidifies the critical place of computational biology and simulations in unraveling the elemental processes of life.
Ruth Nussinov, editor-in-chief of PLOS Computational Biology, discussed the implications following the Nobel announcement.“This Nobel Prize is the first given to work in computational biology, indicating that the field has matured and is on a par with experimental biology. It may also be the very first prize given in any area of the exact sciences for calculations,” noted Nussinov in the PLOS Biology Community Blog.
“In endeavoring to imitate the basic processes of life in silico, great strides are being made toward understanding the secret of life,” continued Nussinov. “Computational biology and simulations, for which Martin Karplus, Michael Levitt, and Arieh Warshel shared the Nobel Prize, can carry the torch leading the sciences to decipher the elemental processes and help alleviate human suffering.”
Understanding how nature works at a very basic level enables scientists the world over to design drugs, unlock the secrets of photosynthesis, and design novel materials. Chemists and scientists are no longer confined to the lab with experiments, but have all of cyberspace to formulate answers to important questions – even ones that haven’t been asked yet.