Profile of Martin Karplus, Michael Levitt, and Arieh Warshel, 2013 Nobel Laureates in Chemistry

You can read the Nobel Prize Web site for the best description of the science behind the 2013 Nobel Prize in Chemistry. However, let me tell you what the beginnings of the science and its immediate impact were really like–a personal account from a close bystander and indirect collaborator in a neighboring field who grew up scientifically with two of the laureates, and knows well the third. The new laureates' papers in the mid-1970s changed the way we think about proteins and set up a new area of science, which immediately and radically influenced and inspired me, along with many others.

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Martin Karplus. Image Copyright Emmanuel Nguyen Ngoc, BnF.

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Michael Levitt. Credit: Linda A. Cicero/Stanford News Service.

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Arieh Warshel.

The 1960s and 1970s were a time of great excitement in the world of proteins. Their amino acid sequences were by then routinely, but laboriously, being determined. The first tranche of 3D structures from X-ray crystallography had been published. And the implications of the structure of DNA and its transcription and translation, and the folding of its protein products were being explored. The center for these activities was the Medical Research Laboratory of Molecular Biology, affectionately called “LMB,” the home of Sydney Brenner, Francis Crick, John Kendrew, Aaron Klug, Cesar Milstein, Max Perutz, and Fred Sanger—all now legends in molecular biology. LMB was small and overcrowded. Theoreticians were crammed side by side in small offices; experimentalists did not have offices, but sat at the end of the bench for paper work. Nobel laureates occupied tiny cubbyholes, and Sydney Brenner and Francis Crick shared a small office. We met all of the time in corridors, and in the canteen for coffee, lunch, and tea. There was continual cross-fertilization of ideas and discussions among the different strands of scientists. Above all, the legendary figures were central to this passionate intellectual activity and drew us, the much younger scientists, in and treated us as equals. They gave us our independence early on and enthusiastically encouraged us by being living examples of what scientists should be. I was recruited at the age of 26, after my one postdoctoral year with W. P. Jencks (another great scientist and man) to work on the mechanism of enzymes, as there was no mechanistic chemist in LMB. I was given a laboratory and a technician and told to do anything I wanted. Independence at that age is now so rare.

Into this milieu came a wunderkind, Michael Levitt, to do a PhD. By great fortune, John Kendrew, a member of the Scientific Academic Advisory Committee of the Weizmann Institute suggested that Levitt go there first to work with Shneior Lifson (1914–2001), as related by Levitt (1). Kendrew realized that the consistent force field that Lifson was working on from data on small crystalline molecules (2) could be applied to macromolecules and analyzed their energetics. Levitt teamed up with Arieh Warshel in Lifson’s laboratory and produced the first real program that could compute noncovalent interaction energies within proteins and nucleic acids, which is the basis of current energy refinement methods (3). The work at the time was rather esoteric and mainly appealed to a small number of X-ray crystallographers.

Warshel then came to work with Levitt at LMB. They collaborated first on enzyme mechanisms, which was my passion. Separately and jointly they came up with ideas that were revolutionary from their calculations on the mechanism of catalysis by hen egg-white lysozyme—a landmark study from David Phillips’ laboratory (4) not from LMB. Phillips was another great scientist who worked hard to further the careers of young scientists. The Phillips paper was remarkable because the mechanism of lysozyme was unknown until the crystal structure had been determined, and the crystallographers proposed a mechanism involving strained interactions in one of the binding sites and electrostatic stabilization of an oxocarbenium ion.

I had come back in 1969 from my postdoctoral year with Bill Jencks, having been exposed to the “strain theory” of enzyme catalysis, dating back to J. B. S. Haldane (5). Many enzymologists believed that enzymes were so sufficiently rigid that they could distort a substrate toward the structure of its transition state, which was the driving force for enzymatic catalysis. However, Levitt’s calculations had shown that this was unlikely. Hidden in a book (6) but fortunately told directly to me, he had written: “Small distortions of a substrate conformation that cause large increases in strain energy cannot be caused by binding to the enzyme.” Warshel and Levitt (7) produced a paper, “Theoretical studies of enzymic reactions: Dielectric, electrostatic, and steric stabilization of the carbonium ion in the reaction of lysozyme,” which calculated the interaction energies in the enzyme–substrate complex (7). Arieh stressed the importance of electrostatic effects in enzymatic catalysis, a theme he has subsequently consistently promoted, and drummed the general importance into me.

Inspired by their work and the early X-ray crystallography, I wrote a book that attempted to synthesize radical, new ideas into a modern look at enzyme mechanisms (8). The Warshel and Levitt key papers and analyses were frequently cited throughout the first and subsequent editions. I coined the term “stress” rather than “strain” because of Warshel and Levitt's calculations. Radically new ideas often take a long while to be accepted (9). Warshel and Levitt's lysozyme paper took considerable time to catch on—the number of citations each year averaged only ∼17 for the first 10 years of publication but has climbed to a remarkable and consistent 120 per annum for the past 10 years; over 2,000 citations in all, so far. Their influence made me write in my book that enzyme mechanisms should be solved by a confederation of chemists and theoreticians, based on structure: “The chemist seeks to identify the chemical nature of the intermediates, by what chemical paths they form and decay, and the types of catalysis that are involved. These results can then be combined with those from X-ray diffraction (and NMR) studies and calculations by theoretical chemists to give a complete description of the mechanism.” That is generally accepted now, but it was not universal in 1977, and different subjects defended their own patches. As an experimentalist, I wanted to acquire experimental data at high structural resolution so the theoreticians could take over. I knew I had gone as far as I could with experiments on catalysis and it required the likes of Warshel who would take it to the next level, which he has done in so many areas since the 1970s and has dominated the field.

In the mid-1970s, promoted by Crick, LMB became interested in the “protein-folding problem.” Levitt and Warshel published a molecular dynamics simulation of the folding of the pancreatic trysin inhibitor (BPTI), based on a simplified representation of protein structure (10). Levitt has subsequently concentrated on protein folding, using both simplified and atomistic models.

I still remember the frisson of excitement when the first paper on the atomistic molecular dynamics simulation of a protein, again BPTI, was published by Martin Karplus and colleagues in Nature in 1977 (11). It was the next landmark in computer simulation of proteins. Karplus was already a young full professor at Harvard, having earned his PhD at the age of 23, and with a famous equation in NMR spectroscopy named after him. Karplus has bestrode the world of theoretical chemistry like a colossus. The list of his former students and postdoctoral scholars looks like a who’s who of theoreticians. And he is a gourmet chef and professional-standard photographer with books and exhibitions to his name.

I listed the Levitt and Lifson (3) 1969 and the McCammon et al. (11) MD simulation as two of the 12 key events in technological innovations in studying the folding of proteins (9). The Karplus and colleagues paper ended with a section: “It is most important to have available detailed tests of the dynamic simulation.” This was where our paths crossed again and I could become part of a confederation between experimentalists and theoreticians. Warshel et al. used an experiment of mine on the energetics of the salt bridge in chymotrypsin to benchmark electrostatic simulations (12). The advent of protein engineering allowed Martin Karplus to calibrate his program CHARMM by simulating the energetics of the mutational energies we had measured on the protein barnase. Valerie Daggett and Levitt performed the first atomistic simulation of protein unfolding in 1992, using Levitt’s program ENCAD (13). This coincided with my introduction of ϕ-value analysis for the experimental near-atomistic analysis of protein folding/unfolding transition states. So began a long collaboration between Daggett and me, combining simulation with experiment, fathered by Levitt.

On a personal note of pride, but with a continuing message, I am Master of a Cambridge College, Gonville and Caius, whose members are numbered in the hundreds, as well as my being at LMB. We elect a few research fellows each year toward the end of their PhD so they can do independent postdoctoral work in the sciences and the humanities. Four have gone on to win Nobel Prizes, including Roger Tsien, and now Michael Levitt. And we did have Francis Crick as a mature graduate student. The message is, we must allow scientists to be independent when they are young and not wait until they are in their 30s and 40s for their first independent grants. To me, all three of this year's winners deserved their Nobel Prizes just for their earlier work, and have taken it to even greater heights since. The prize is a triumph for youth. Martin Karplus earned his PhD at an age when many are just starting it. Michael Levitt and Arieh Warshel showed what young scientists can achieve in a laboratory that fosters talent and independence.