Computational chemistry wins Nobel Prize

Computer modelling of molecules has gained the Nobel Prize in Chemistry for 2013. According to the official citation, the three Nobellists – Martin Karplus of the Université de Strasbourg, France and Harvard University, USA; Michael Levitt of Stanford University School of Medicine, Stanford, USA; and Arieh Warshel of the University of Southern California, Los Angeles, USA – received the award ‘for the development of multi-scale models for complex chemical systems’.

Karplus, Levitt, and Warshel developed a way of modelling complex molecules by using approximations from Newtonian physics alongside quantum chemistry calculations. The strength of classical physics was that calculations were simple and could be used to model really large molecules. However, it offered no way to simulate chemical reactions. But calculations of chemical reactions, using quantum mechanics, required enormous computing power and could therefore only be carried out for small molecules.

According to a statement from the Royal Swedish Academy of Sciences, which decides the award, ‘this year’s Nobel Laureates in chemistry took the best from both worlds and devised methods that use both classical and quantum physics. For instance, in simulations of how a drug couples to its target protein in the body, the computer performs quantum theoretical calculations on those atoms in the target protein that interact with the drug. The rest of the large protein is simulated using less demanding classical physics.’

However, one of the reasons for the award was, as the Academy noted: ‘The strength of the methods that Karplus, Levitt, and Warshel have developed is that they are universal. They can be used to study all kinds of chemistry; from the molecules of life to industrial chemical processes.’

Modern chemical research tends to focus on molecular function but this is difficult to ascertain experimentally. Isotope labelling and femtosecond spectroscopy can give clues, but rarely produce conclusive evidence for a given mechanism in complex systems, such as catalysis (which is of huge commercial and industrial importance) and almost all biochemical processes. Theoretical modelling is therefore indispensable as an adjunct to experiment.

Chemical processes are mediated by a transition state, a configuration with the lowest possible (free) energy that links the product with the reactant, but this state is not normally accessible to experiment, but there are theoretical methods to search for such structures. Consequently, theory is a necessary complement to experiment and the work awarded this year´s Nobel Prize in Chemistry developed methods, using both classical and quantum mechanical theory, to model large complex chemical systems and reactions.

The classical component of the model contains many fewer degrees of freedom and the physics is much simpler -- consequently this aspect can be calculated much faster on a computer. The key accomplishment was to show how the two regions in the modelled system can be made to interact in a physically meaningful way. Frequently the entire molecular system is embedded in a dielectric continuum.

The first step in the development of multi-scale modelling was taken when Warshel visited Karplus at Harvard in the beginning of the 1970s. Warshel had a background in inter- and intra-molecular potentials and Karplus had the necessary experience in quantum chemistry. Together they constructed a computer program that could calculate the π-electron spectra and the vibration spectra of a number of planar molecules with excellent results. The basis for this approach was that the effects of the σ-electrons and the nuclei were modelled using a classical approach and that the π-electrons were modelled using a PPP (Praiser –Parr –Pople) quantum-chemical approach corrected for nearest overlap.

This was the first hybrid model, but it was restricted to planar systems where symmetry makes a natural separation between the π-electrons that were described quantum chemically and the σ-electrons that were handled by the classical model. However, this was not a limitation in principle – as Warshel and Levitt showed a few years later, in 1976, by constructing a general scheme for a partitioning between electrons that are included in the classical modelling and electrons that are explicitly described by a quantum chemical model.

The methodology has been used to study not only complex processes in organic chemistry and biochemistry, but also for heterogeneous catalysis and theoretical calculation of the spectrum of molecules dissolved in a liquid. But most importantly, according to the Swedish Royal Academy, ‘it has opened up a fruitful co-operation between theory and experiment that has made many otherwise unsolvable problems solvable.’

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