Abstract
Despite the enormous advances in structural studies of biological systems, people 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. In this lecture, the speaker will review the progress in simulating biological functions, starting with the early stages of the field and the development of hybrid quantum mechanics/molecular mechanics (QM/MM) approaches for simulations of enzymatic reactions. He provides overwhelming support to the idea that enzyme catalysis is due to electrostatic preorganization and then moves to the renormalization approaches aimed at modeling long time processes, demonstrating that dynamical effects cannot change the rate of the chemical steps in enzymes. The speaker will also describe the use of electrostatic augmented coarse grained (CG) model developed by him and his collaborators and the renormalization method to simulate the action of different challenging complex systems. It is shown that the CG model produces, for the first time, realistic landscapes for vectorial process such as the actions of F1 ATPase, F0 ATPase and myosin V. 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 human’s knowledge, these studies are the only studies that reproduced consistently (rather than assumed) a structure based vectorial action of molecular motors. The speaker will describe a breakthrough in CG modeling of voltage activated ion channels and will also 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 their CG approach. The emerging finding from all of the simulations is that electrostatic effects are the key to generating functional free energy landscapes. Finally, he will present some thought on the future of the field, taking drug resistance as an example.
About the speaker
Prof Arieh Warshel received his BSc degree in Chemistry from Technion, Haifa in 1966. Subsequently, he obtained both MSc and PhD degrees in Chemical Physics (in 1967 and 1969, respectively) from the Weizmann Institute of Science, Israel. He then joined Harvard University to further his postdoctoral work until 1972 and returned to the Weizmann Institute. In 1976, he joined the University of Southern California and is currently the Dana and David Dornsife Chair in Chemistry and also the Distinguished Professor of Chemistry and Biochemistry.
Prof Warshel's research covers a wide range of problems in modern biophysical chemistry. He and his coworkers have pioneered several of the most effective models for computer simulations of biological molecule. The studies of his group include simulations of enzyme catalysis and protein action; simulation of chemical reactions in solution; electrostatic energies in macromolecules; and protein folding.
Prof Warshel was awarded the 2013 Nobel Prize in Chemistry, jointly with Prof Martin Karplus of Harvard University and Prof Michael Levitt of Stanford University, for their work to make Newton’s classical physics work side-by-side with the fundamentally different quantum physics. They 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.
In addition, Prof Warshel received numerous of awards including the Annual Award of the International Society of Quantum Biology and Pharmacology (1993); Tolman Medal (2003); President’s award for computational biology from the ISQBP (2006); RSC Soft Matter and Biophysical Chemistry Award (2012); the Founders Award of the Biophysical Society (2014); and the 2013 Israel Chemical Society Gold Medal (2014). He was also elected a member of the US National Academy of Sciences (2009) and fellow of the Royal Society of Chemistry (2008); the Biophysical Society (2000); and the American Association for the Advancement of Science (2012).
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