Arieh Warshel

Warshel was born on November 20, 1940, at Kibbutz Sde-Nahum, in Palestine, later Israel.[1] The kibbutz is in the Beit She’an Valley.[3] He served in the Israel Defense Forces and attained the rank of captain before pursuing his university education in chemistry.[4]

Warshel later described his choice of chemistry as almost accidental: a fellow soldier who had abandoned plans to study the subject because of poor eyesight suggested that Warshel study it instead.[5] His decision to leave the kibbutz was partly connected to its expectations concerning higher education; he recalled that its leaders wanted members to contribute two years of work to the community for every year spent studying.[5]

He studied chemistry at the Technion–Israel Institute of Technology in Haifa, receiving his bachelor’s degree in 1966.[1] He graduated summa cum laude.[4] During his third undergraduate year, a project on enzymes—substances that accelerate chemical reactions—prompted him to ask how they produced that acceleration.[5] Warshel later identified this question as one of the subjects underlying the research recognized by his Nobel Prize.[5]

After reading about Shneior Lifson, a professor at the Weizmann Institute of Science who lived in a neighboring kibbutz, Warshel approached him and was accepted into his research group.[5] At Weizmann, in Rehovot, he earned a master’s degree in 1967 and a doctorate in chemical physics in 1969.[1] Recalling the pace of his graduate education, Warshel said he completed his master’s work in half a year before Lifson moved him directly into doctoral study.[5]

As a doctoral student working with Lifson, Warshel began collaborating with Michael Levitt during the 1960s.[6] Their work used the Weizmann Institute’s Golem computer to develop a program for modeling molecules, with particular relevance to large biological molecules.[6] Warshel’s early collaboration with Levitt used classical physics to represent molecular behavior.[1] These investigations preceded his later work with Martin Karplus on combining classical molecular modeling with quantum-mechanical calculations.[1]

In 1970, Warshel joined Martin Karplus at Harvard University as a postdoctoral fellow and remained a research fellow there until 1972.[1] Karplus had been developing computer programs that applied quantum mechanics to chemical reactions, while Warshel brought experience in molecular modeling based on classical physics.[1] Their collaboration produced a program that treated molecular nuclei and some electrons classically while using quantum mechanics for other electrons.[1]

The two approaches addressed different computational needs.[2] Programs based on classical physics could represent large molecules at rest, but they could not capture the subatomic dynamics involved in chemical reactions.[2] Quantum-physics programs could describe those dynamics, but applying them to entire molecules demanded too much computing power.[2] Combining the approaches made it possible to reserve the more demanding calculations for the part of a molecular system directly involved in a reaction while using classical physics elsewhere.[2]

Warshel’s earlier work with Lifson and Levitt included molecular representations that he later described as balls connected by springs.[5] He recalled that their program circulated among laboratories before commercial companies copied the original software, and that later versions could represent complex molecules such as proteins.[5] Warshel and Lifson also developed the Consistent Force Field method, which incorporated quantum considerations into molecular simulations and proved useful in their collaboration with Levitt.[7]

Representing molecular structure was not the same problem as representing enzyme activity.[5] A spring-based model could describe aspects of a molecule’s structure, but an enzymatic reaction involved chemical bonds breaking and forming, requiring treatment beyond that simple representation.[5] In the combined approach developed by Warshel and his collaborators, classical physics tracked atomic motion while quantum physics described the breaking and formation of chemical bonds.[8] Their computer simulations in the 1960s and 1970s offered a way to investigate rapidly occurring, complex reactions, including combustion and photosynthesis, rather than relying on physical ball-and-stick models alone.[8]

The early hybrid technique had a significant limitation: it initially applied only to molecules with mirror symmetry.[1] Karplus was particularly interested in retinal, a complex molecule in the eye that is crucial to vision and changes shape when exposed to light.[1] In 1974, Warshel, Karplus, and their collaborators successfully modeled that light-induced change in shape.[1] The retinal research brought classical modeling and quantum physics together in a calculation concerned with the behavior of a biologically important molecule.[6]

Warshel returned to the Weizmann Institute as a research associate in 1972 and resumed his collaboration with Levitt.[1] They developed a later program that could be applied to any kind of molecule and made it more efficient by concentrating computational effort on the molecule’s more interesting parts.[6] The pair also used simulations to investigate how proteins work.[6] From 1974 to 1976, Warshel was a visiting scientist at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, where he again worked with Levitt.[1]

In 1975, Warshel and Levitt published a simulation of protein folding.[1] Their investigations also addressed enzyme reactions, leading them to devise a scheme that represented some parts of an enzyme with classical physics and others with quantum mechanics.[1] The scheme accounted for interactions between those differently modeled components, as well as interactions between both components and the surrounding medium.[1] It therefore included not only the region undergoing the chemical change but also its relationship with the larger molecular environment.[1]

In 1976, Warshel and Levitt applied their general scheme to the first computer model of an enzymatic reaction.[1] Their approach was not restricted to the particular enzyme reaction they modeled: the scheme could be used for any molecule.[1] The computational method combined quantum-mechanical analysis of a limited region with a classical, Newtonian treatment of the surrounding molecular system.[9] This division addressed the contrast between quantum methods, which could supply detailed calculations for relatively few particles, and broader approaches that could represent many molecules while providing less particle-level detail.[9]

The retinal and enzyme projects formed two strands in the development of the combined method.[2] One program, created by Karplus and Warshel, investigated the human retina; another, created by Warshel and Levitt, modeled enzyme reactions.[2] The resulting system applied computationally demanding quantum calculations to electrons and atomic nuclei directly involved in a reaction, while classical calculations represented the rest of the molecule.[2] This arrangement made it possible to study chemical processes without treating every part of a large molecular system at the same computational level.[2]

Warshel joined the chemistry department at the University of Southern California as an associate professor in 1976.[1] His Weizmann appointment ended in 1978, when he held the rank of associate professor there.[1] At USC, he became a full professor in 1984 and a distinguished professor in 2011.[1] At the time of the 2013 Nobel announcement, he was a distinguished professor of chemistry and biochemistry and had been at the university since 1976.[3] His academic work has also been identified with theoretical chemistry and biophysics.[10]

His research encompasses computational biochemistry and biophysics, particularly the use of computers to simulate biological functions.[4] He developed the field known as computational enzymology, including numerical simulations of enzyme reaction mechanisms.[4] A stated aim of that work was to use quantitative simulations to generate qualitative knowledge and discoveries.[4] Rather than treating a protein’s structure as the endpoint of an investigation, Warshel sought to use that structure to explain the protein’s activity.[3]

Discussing his research after the Nobel announcement, Warshel said that curiosity had been a principal motivation.[3] He described the method as a way for a computer to use a protein’s structure to explain what it does, giving digestion as an example of a biological function such calculations could help explain.[3] He also said that understanding how a protein works could assist scientists in designing drugs.[3] In a separate 2013 interview, he placed the central discovery in 1975 but emphasized the long process of demonstrating it: “The discovery itself was in 1975, but it took many years to prove.”[6]

Warshel continued to distinguish between the possibilities of computational enzymology and the accuracy already achieved by his group.[5] In a 2019 interview, he said its enzyme model had not yet reached the precision he considered necessary to predict new active enzymes for drugs.[5] The group was testing the model against chemical reactions whose outcomes were already known.[5] Its goals included calculating reaction-energy changes with an accuracy of one kilocalorie.[5]

The same interview described research using a more approximate model to investigate larger biological mechanisms.[5] One example concerned a receptor involved in insulin production in the pancreas.[5] Warshel thus described work at different levels of approximation: detailed enzyme calculations being tested against known reactions, and more approximate calculations directed at larger biological systems.[5] In 2022, he characterized his group’s computational method as correlating the structure and function of biological molecules and said that such methods had become important in medically related research.[11]

Warshel has held both Israeli and United States citizenship.[12] When the Nobel Prize was announced, he said he still defined himself as Israeli, although he also called that identity “not a clear definition.”[13] In another interview, he described having both Israeli and American passports, behaving like an Israeli, speaking Hebrew, and sometimes switching to English.[13] He also emphasized that he continued to see good science being done in Israel.[13]

Warshel shared the 2013 Nobel Prize in Chemistry with Martin Karplus and Michael Levitt “for the development of multiscale models for complex chemical systems.”[2] The award recognized computer programs capable of simulating and predicting chemical processes by bringing classical physics and quantum mechanics into the same modeling framework.[2] All three laureates had received support from the United States National Science Foundation.[2]

The models addressed a problem central to calculations of large chemical systems: classical physics made calculations for large molecules practical, while quantum physics could describe chemical reactions but required much greater computing power.[12] Their combined method allowed a chemically active region to receive quantum treatment while the larger surrounding system was represented with less demanding classical calculations.[12] It provided a way to study systems that neither small-scale quantum calculations nor broad classical approaches could fully describe on their own.[12]

A drug binding to a target protein illustrates this division of computational effort.[12] Quantum calculations can be applied to the atoms interacting with the drug, while classical physics represents the rest of the protein.[12] The approach retains a detailed description where the interaction occurs without imposing the same computational demands on the entire protein.[12] This example connects the method’s underlying physical framework with the biological and drug-development applications discussed in accounts of Warshel’s work.[9][12]

His contribution to computational enzymology likewise centered on connecting numerical calculations with explanations of biological function.[4] Simulations of enzyme reaction mechanisms were intended not simply to reproduce molecular representations but to generate knowledge about how biological processes work.[4] The progression from molecular modeling to simulations of retinal, protein folding, and enzymatic reactions encompassed several distinct applications of computational chemistry.[1] The general enzyme-modeling scheme also included the surrounding medium, making interactions beyond the immediately reacting components part of the calculation.[1]

The scientific development recognized by the Nobel Prize had substantial roots in Warshel’s Israeli education and research.[6] His collaboration with Levitt began at the Weizmann Institute while he was a doctoral student working with Lifson, and their early molecular-modeling program ran on the institute’s Golem computer.[6] After working with Karplus at Harvard, he reunited with Levitt at Weizmann in 1972.[6] Speaking to Israeli president Shimon Peres after the 2013 award, Warshel said the research that earned him the prize had been conducted in Israel.[6]

Recognition of Warshel’s scientific career also includes membership in the United States National Academy of Sciences and the Biophysical Society, and fellowship in the Royal Society of Chemistry.[4] His USC career included promotion to full professor in 1984 and appointment as a distinguished professor in 2011, before the Nobel award.[1] Together with the prize, these appointments and memberships form part of the institutional recognition of his work in computational chemistry, biochemistry, and biophysics.[1][4]

Warshel’s departure from the Weizmann Institute became a subject of public discussion after the Nobel announcement.[14] He said it had been difficult to progress there and that he left because he had not received tenure, describing a need to seek a more secure academic future abroad.[14] The institute responded that he “would most certainly have advanced” had he stayed.[14] These accounts presented different assessments of the academic prospects available to him at Weizmann.[14]

Warshel has also criticized the reception and attribution of his early research.[11] In 2022, he said: “My key idea and results were originally considered to be incorrect and then termed as trivial ideas that were persistently attributed to others.”[11] This was his retrospective characterization of the difficulties surrounding the acceptance and recognition of his work.[11]