Arieh Warshel

In 2013, Arieh Warshel, Distinguished Professor of Chemistry and Biology at the University of Southern California’s Dornsife College of Letters, Arts and Sciences, was awarded a Nobel Prize for Chemistry for his groundbreaking research in theoretical chemistry. Dr. Warshel holds the Dana and David Dornsife Chair in Chemistry at USC, where he has served on the faculty since 1976.

A member of the National Academy of Sciences, and a Foreign Member of the Russian Academy of Sciences, Dr. Warshel has pioneered computer simulations of the functions of biological molecules. He has authored over 500 peer-reviewed articles, including the book, Computer Modeling of Chemical Reactions in Enzymes and Solutions (Wiley Professional, 1991). He co-developed computer programs for molecular simulations which have been used extensively in different applications including the development of new pharmaceuticals.

He and his colleagues have pioneered key approaches for simulating the functions of biological molecules, including introducing molecular dynamics in biology; developing the quantum-mechanical/molecular-mechanical (QM/MM) approach; introducing simulations of enzymatic reactions; pioneering microscopic simulations of electron transfer and proton transfer in solutions and in proteins; pioneering microscopic modeling of electrostatic effects in macromolecules; and introducing simulations of protein folding. In addition, Dr. Warshel and his collaborators recently elucidated the structure-based origin of the vectorial action of molecular machines.

An honorary member of the Royal Society of Chemistry (RSC), Dr. Warshel’s numerous awards include the American Chemical Society’s Tolman Medal, the RSC’s Soft Matter and Biophysical Chemistry Award, and the Biophysical Society’s Founders Award.

Research

Warshel is responsible for many of today's key multiscale simulation approaches in modeling the functions of biological molecules. These advances include: co-developing (with M. Levitt) (JMB 1976) and then advancing the hybrid QM/MM approach, which is now used extensively in modeling enzymatic reactions (that has been recognized by the 2013 Nobel Prize for Chemistry); co-developing (with Levitt and Lifson) the Cartesian Consistent Force Field, which has been the basis of most current modeling programs; Developing the first physically consistent microscopic approach for calculations of electrostatic energies in proteins, including the illustration of the importance of the self-energy term and the role of the protein’s permanent dipoles; co-developing (with M. Levitt) a simplified coarse grained (CG) model for protein folding, which is now widely used; Developing the empirical valence bond (EVB) mode,  which is now used widely, and finally, moving from the early CG model to a more general electrostatic enhanced CG model, which appears to provide a very powerful way of modeling the function of molecular machines. His early studies of proton transfer (PT) and electron transfer (ET) have led to the introduction of very powerful approaches for microscopic simulations of ET (the development of the microscopic equivalent of Marcus parabolas). Similarly, Warshel developed the EVB model (empirical valence bond), as arguably the most effective method of modeling PT (proton transfer) in condensed phases and proteins. Subsequently, he and his team have developed very powerful approaches for simulating long timescale PT processes. The methodological progress outlined above has allowed us to make major contributions in elucidating the nature of the primary event in photosynthesis and to present early simulations of PT in key biological systems. His group contunues to make key contributions in the studies of electrostatic effects in biological systems. This progress places them in a pivotal position to move towards gaining quantitative insight about of the molecular nature of ET, PT and ion transport in biological systems. These accomplishments have been drastically augmented recently by the major progress in using CG models in studies of molecular machines involving in energy conversion, and transport of charges, protons and even proteins. The majority of this research has bridged the gap between chemistry and biology, where perhaps the clearest link is provided by our Group's advances in paving the way for quantitative modeling enzymatic reactions, which are chemical reactions in biological molecules.

Contribution to Science

Dr. Warshel has been involved in paving the way to many of the key multiscale simulation approaches ^{[1] [2]} in modeling the functions of biological molecules. These advances include the development of the QM/MM approach ^[3] for modeling enzymatic reactions. (Recognized in the 2013 Nobel Prize for Chemistry). His progress in this field involved the development of the EVB method and more recently the pardynamics (PD) approach ^[4] that allow us to generate quantitative ab initio free energy surfaces using the EVB as a reference potential, including new innovations ^[5]. He developed the first physically consistent microscopic approach for calculations of electrostatic energies in proteins and continued in leading the field of studying the electrostatic basis of biological functions ^[6]. He also co-developed in 1975 coarse grained (CG) for protein folding. The combination of this model with our electrostatic models led to very powerful CG model ^[2] that has been refined in recent years, including for protein stability in solutions and in membranes ^[7]. Warshel discovered what is likely the most important factor in enzyme catalysis; namely the electrostatic preorganization ^{[8] [9]}. He and his co-workers have studied all the proposals for the catalytic power of enzymes ^[10]. In 1976, Warshel performed the first molecular dynamics (MD) simulations of a biological process ^[10] and continued in advancing free energy perturbations in enzymes and microscopic simulations of electron an proton transfer reactions and subsequently in developing long time simulations including the renormalization model, Langevin dynamics and time-dependent Monte Carlo approaches for multiscale models of enzymes, proton pumps, motors and ion channels ^[2]. He pioneered and further advanced studies of key biological systems ranging from G-proteins ^{[11] [12]}, DNA polymerases ^[11] and other systems ^[2].

Seminal Publications

1. S. Lifson & A. Warshel (1968) Consistent Force Field for Calculations of Conformations Vibrational Spectra and Enthalpies of Cycloalkane and N-Alkane Molecules. Journal of Chemical Physics 49(11):5116, doi:10.1063/1.1670007.
2. M. Levitt & A. Warshel (1975) Computer-Simulation of Protein Folding. Nature 253(5494):694, doi:10.1038/253694a0.
3. A. Warshel (1976) Bicycle-Pedal Model for 1st Step in Vision Process. Nature 260(5553):679, doi:10.1038/260679a0.
4. A. Warshel & M. Levitt (1976) Theoretical Studies of Enzymic Reactions - Dielectric, Electrostatic and Steric Stabilization of Carbonium-Ion in Reaction of Lysozyme. Journal of Molecular Biology 103(2):227, doi:10.1016/0022-2836(76)90311-9.
5. Warshel, A. (1984). Simulating the Energetics and Dynamics of Enzymatic Reactions. In: Chagas, C., Pullman, B. (eds) Specificity in Biological Interactions. Springer, Dordrecht. doi.org/10.1007/978-94-009-6457-0_4
6. Calculations of Electrostatic Interactions in Biological Systems and in Solutions, A. Warshel and S. T. Russell, Quarterly Review of Biophysics 17, 283-422 (1984).
7. S. Creighton, J. K. Hwang, A. Warshel, W. W. Parson, & J. Norris (1988) Simulating the Dynamics of the Primary Charge Separation Process in Bacterial Photosynthesis. Biochemistry 27(2):774, doi:10.1021/bi00402a043.
8. A. Warshel & W. W. Parson (1991) Computer-Simulations of Electron-Transfer Reactions in Solution and in Photosynthetic Reaction Centers. Annual Review of Physical Chemistry 42:279, doi:10.1146/annurev.physchem.42.1.279.
9. A. Warshel (2002) Molecular Dynamics Simulations of Biological Reactions. Accounts of Chemical Research 35(6):385, doi:10.1021/ar010033z.
10. A. Warshel, P. K. Sharma, M. Kato, Y. Xiang, H. Liu, & M. H. M. Olsson (2006) Electrostatic Basis for Enzyme Catalysis. Chemical Reviews 106(8):3210, doi:10.1021/cr0503106.
11. S. C. L. Kamerlin, P. K. Sharma, R. B. Prasad, & A. Warshel (2013) Why Nature Really Chose Phosphate. Quarterly Reviews of Biophysics 46(1):1, doi:10.1017/s0033583512000157.
12. I. Kim & A. Warshel (2013) Coarse-Grained Simulation of the Gating Current in the Voltage-Activation Kv1.2 Channel. Proceedings of the National Academy of Sciences of the United States of America 111:2128-2133, doi:10.1073/pnas.1324014111
13. S. Mukherjee & A. Warshel (2015) Dissecting the role of the γ-subunit in the rotary-chemical coupling and torque generation of F1-ATPase. Proceedings of the National Academy of Sciences of the United States of America 112:2746-2751, doi:10.1073/pnas.1500979112
14. Alhadeff R, Vorobyov I, Yoon HW, Warshel A. Exploring the free-energy landscape of GPCR activation. Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10327-10332. doi: 10.1073/pnas.1810316115. Epub 2018 Sep 26. PubMed PMID: 30257944; PubMed Central PMCID: PMC6187162.