Ariel Warshel delivers the UNSW Howard Nobel Laureate Lecture

Posted 30 June 2016

Arieh Warshel is a Distinguished Professor of Chemistry at the University of Southern California. Together with together with Michael Levitt and Martin Karpluse, Warshel was awarded the 2013 Nobel Prize in Chemistry for the development of multiscale models for complex chemical systems. His research is aimed at providing microscopic description to the action of biological molecules and other complex systems.

Warshel received his BSc Chemistry (Technion, Israel), MSc and PhD Chemical Physics (Weizmann Institute of Sciences, Israel). Major honours: Nobel Laureate (Chemistry, 2013), Member National Academy of Sciences (2009), Honorary Fellow of the Royal Society of Chemistry (2008), Fellow of the Biophysical Society (2000). 

This is a unique opportunity to hear a lecture from a pioneer in computational modelling applied to complex biological systems. UNSW Law Building G04, 3-4 pm, 1 July 2016.

The studies of biological systems have advanced enormously due to the progress in structural and biochemical research. However, we are frequently left without a clear structure function correlation and cannot fully describe how different systems actually work. This introduces a major challenge for computer modeling approaches that are aimed at a realistic simulation of biological functions. The unresolved questions range from the elucidation of the basis for enzyme action to the understanding of the directional motion of complex molecular motors. Here the progress in simulating biological functions will be reviewed, starting with the early stages of the field and the development of QM/MM approaches for simulations of enzymatic reactions (1). We provide overwhelming support to the idea that enzyme catalysis is due to electrostatic preorganization and then move to the renormalization approaches aimed at modeling long time processes, demonstrating that dynamical effects cannot change the rate of the chemical steps in enzymes (2). Next we describe the use our electrostatic augmented coarse grained (CG) model (2) and the renormalization method to simulate the action of different challenging complex systems. It is shown that our CG model produces, for the first time, realistic landscapes for vectorrial process such as the actions of F1 ATPase (3,4), F0 ATPase (5) and myosinV (6). It is also shown that such machines are working by exploiting free energy gradients and cannot just use Brownian motions as the vectorial driving force. Significantly, at present, to the best of our knowledge, theses studies are the only studies that reproduced consistently (rather than assumed) a structure based vectorial action of molecular motors. We also describe a breakthrough in CG modeling of voltage activated ion channels (7) and outline a recent simulation of the tag of war between staled elongated peptide in the ribosome and the translocon as an illustration of the power of our CG approach (8). The emerging finding from all of our simulations is that electrostatic effects are the key to generating functional free energy landscapes. Finally we present some thought on the future of the field, taking drug resistance as an example (9).

1    Electrostatic Basis for Enzyme Catalysis, A. Warshel, P. K. Sharma, M. Kato, Y. Xiang, H. Liu and M. H. M. Olsson, Chem. Rev., 106, 3210 (2006).
2    Coarse-Grained (Multiscale) Simulations in Studies of Biophysical and Chemical Systems, S. C.   L.Kamerlin, S. Vicatos, A. Dryga and A. Warshel, Ann. Rev. Phys. Chem. 62,41 (2011).
3    Electrostatic Origin of The Mechanochemical Rotary Mechanism And The Catalytic Dwell of F1-ATPase, S. Mukherjee and A.Warshel, Proc. Natl. Acad. Sci. USA ,108,  20550 (2011).
4    Torque, chemistry and efficiency in molecular motors: a study of the rotary–chemical coupling in F1-ATPase, S. Mukherjee, R. B.Prasad  and A. Warshel, QRB Discovery, 48, 395–403 (2015).
5    Realistic simulations of the coupling between the protomotive force and the mechanical rotation of the F0-ATPase, Proc. Natl. Acad. Sci. USA, 109,14876 (2012).
6     Electrostatic origin of the unidirectionality of walking myosin V motors, S. Mukherjee and  A. Warshel, Proc. Natl. Acad. Sci. USA, 110, 17326-17331 ( 2013).
7    Converting Structural Information Into an Allosteric-Energy-Based Picture for Elongation Factor Tu Activation by The Ribosome, A. J. Adamczyk and A. Warshel, Proc. Natl. Acad. Sci. USA, 108, 9827 (2011).
8    Simulating the pulling of stalled elongated peptide from the ribosome by the translocon, A. Rychkova, S. Mukherjee, R. P. Bora, and A.  Warshel,  Proc. Natl. Acad. Sci. USA, 110, 10195-10200  (2013) .
9    Prediction of Drug Resistance muation of HIV Protease, H. Ishikita and A. Warshel, Angew. Chem. Int. Ed., 47, 697-700 (2008)..