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The Nobel Prize in Chemistry 2013: Using computers to understand biological catalysts

25 October 2013

Understanding exactly what it is that makes enzymes such good catalysts will help develop new drugs and new ways of making molecules. Computer simulations provide a way to 'see' a chemical reaction taking place in the heart of the complex protein structure of an enzyme, showing the subtle atomic details of biochemical reactions, using the molecular simulation methods developed by this year's winners of the Nobel Prize in Chemistry, Martin Karplus, Michael Levitt and Arieh Warshel.

Structures from QM/MM modelling of enzyme-catalysed reactionsEnzymes are Nature's chemists, making life possible by speeding up chemical reactions enormously. Evolution has made them into outstandingly good catalysts, capable of making specific biochemical transformations happen very quickly. We can't yet make protein catalysts remotely as good as natural enzymes, though. Understanding exactly what it is that makes enzymes such good catalysts will help develop new drugs and new ways of making molecules. But how to 'see' a chemical reaction taking place in the heart of the complex protein structure of an enzyme? Computer simulations provide a way to do this, showing the subtle atomic details of biochemical reactions, using the molecular simulation methods developed by this year's winners of the Nobel Prize in Chemistry, Martin Karplus, Michael Levitt and Arieh Warshel. They developed tools, and showed how it was possible to simulate chemical reactions in enzymes. They did this by combining classical 'ball and spring' models of molecules with quantum mechanics. Classical 'molecular mechanics' methods represent molecules by balls and springs, and can now do a very good job of modelling protein structure and dynamics, but chemical reactions involve the rearrangement of electrons, an inherently quantum mechanical problem. The Nobel Laureates joined together quantum mechanics and molecular mechanics to create hybrid quantum mechanics/molecular mechanics (QM/MM) methods. For an enzyme, the small 'active site', where the reaction happens, is treated by QM, while the rest of the protein is modelled by MM. This shows how chemical bonds are made and broken, and how an enzyme can lower the energy barrier to the reaction - the secrets of catalysis. These QM/MM methods are now used to understand and predict how drugs are broken down in the body and to look at fundamental principles of catalysis, for example to study the effects of protein dynamics. The molecular-level insight they give into biological processes are helping to develop new medicines and will help in emerging areas like the design of novel protein catalysts. It used to be said that to study enzymes, what you needed was a piece of liver and a razor blade. Now, thanks to the work of Karplus, Levitt and Warshel, computers are an essential tool for biochemists working to understand Nature's fantastic catalysts. 

Two of the Laureates have connections to the School of Chemistry:  Martin was a Benjamin Meaker Visiting Professor in Bristol in 2000, and Arieh an RSC Award Lecturer here in 2012; both also have been Plenary Speakers at the Computational Molecular Science conferences organized by our Centre for Computational Chemistry (2008 and 2010, respectively). Prof. Warshel hosted a research visit Ewa Chudyk, a PhD student in the Centre for Computational Chemistry in 2012, while Prof. Adrian Mulholland worked on QM/MM methods as a postdoctoral fellow with Prof. Karplus, and Dr. David Glowacki develops and implements methods in Prof. Karplus's CHARMM biomolecular simulation program.  

Related articles:

The Nobel Prize in Chemistry 2013 <http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2013/press.html>

Computational Molecular Science 2008  <http://www.chm.bris.ac.uk/cms/cms2008/index.html>

Computational Molecular Science 2010  <http://www.chm.bris.ac.uk/cms/cms2010/index.html>

Molecular modelling to help create better, safer drugs <http://www.bristol.ac.uk/news/2013/9410.html>

Enzyme catalysis unmasked in new research <http://www.bristol.ac.uk/news/2013/9855.html>