NOBEL PRIZE IN CHEMISTRY - COMPUTATIONAL BIOLOGY AT CENTER STAGE



The 2013 Nobel Prize in Chemistry was awarded to Martin Karplus, Michael Levitt, and Arieh Warshel for the "development of multiscale models for complex chemical systems." This award has marked a major turning point for computational biology through recognition that computation transforms the way scientists study the structure and function of biochemical molecules.

The seminal work attributed to the development of multiscale modeling began in the 1970's when Warshel joined Karplus's lab at Harvard as a postdoctoral fellow. Warshel had just completed his doctorate in chemical physics at the Weizmann Institute of Science in Rehovot, Israel, where he worked under the guidance of Shneior Lifson to develop methods to calculate consistent force fields of molecules^1,2. Lifson, who passed away in 2001, is considered a founding father of computational structural biology and also mentored Levitt as a young student. Karplus had expertise in applying quantum mechanics to chemical reactions. Together they developed a computer program that used a combination of classical and quantum mechanical calculations to consistently determine the ground and excited state potentials of complex molecules³. This was the first time that classical and quantum mechanics were used together to model complex molecules, and a similar method was also used to calculate changes in the conformation of retinal isomers upon photoactivation^4,5. This novel approach was based on partitioning electrons in planar molecules such that Π-electrons were modeled using quantum chemical calculations and σ-electrons and nuclei modeled using classical mechanics.

Warshel returned to Weizmann after his postdoctoral training and started working with Levitt, who had also come back to Weizmann after completing a research fellowship at Cambridge University. Their groundbreaking work involved developing a universal scheme to partition electrons in a molecule that are modeled using classical or quantum approaches. This hybrid quantum mechanics/molecular mechanics approach made it possible to model chemical reaction and complex molecules like proteins by combining the accuracy of quantum mechanics and the speed of classical molecular mechanics . They used this hybrid approach to model how lysozyme cleaves a glycoside chain. Levitt and Warshel also developed computational methods to study the folding of bovine pancreatic trypsin inhibitor by grouping atoms that could be modeled classically in rigid "pseudoatoms," which greatly enhanced the speed by which folding could be modeled .

The work of Karplus, Levitt, and Warshel formed the foundation of molecular modeling and has been essential to moving forward research in both theoretical and experimental chemistry and biochemistry. Levitt, a previous keynote speaker at the 3Dsig satellite meeting of ISMB, as well as Karplus and Warshel have been honored with lifetime membership in ISCB in recognition of this achievement.

References

¹Lifson S, Warshel A. (1968). A Consistent Force Field for Calculation on Conformations, Vibrational Spectra and Enthalpies of Cycloalkanes and n-Alkane Molecules. J. Phys. Chem. 49 (11): 5116.

²Warshel A, Lifson S. (1970). Consistent Force Field Calculations. II. Crystal Structure, Sublimation Energies, Molecular and Lattice Vibrations, Molecular Conformations and Enthalpies of Alkanes. J. Chem. Phys. 53 (2): 582.

³Warshel A, Karplus M. (1972). Calculation of ground and excited state potential surfaces of conjugated molecules. I. Formulation and parametrization. J. Am. Chem. Soc. 94 (16): 5612.

⁴Rowan R, Warshel A, Sykes BD, and Karplus M. (1974). Conformation of Retinal Isomers. Biochemistry. 13(5): 970.

⁵Warshel A, Karplus M. (1974). Calculation of pi-pi excited state conformations and vibronic structure of retinal and related molecules. J. Am. Chem. Soc. 96(18):5677.

⁶Warshel, A; Levitt, M (1976). Theoretical studies of enzymic reactions: Dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. J. Mol. Biol. 103 (2): 227.

⁷Levitt M, Warshel A. (1975). Computer simulation of protein folding. Nature. 253: 694.