Enzymes 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 the winners of the 2013 Nobel Prize in Chemistry, Martin Karplus, Michael Levitt and Arieh Warshel. These methods combine 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 for synthetic biology. 

Project lead: Professor Adrian Mulholland (biomolecular simulation, computational enzymology, combined quantum mechanics/molecular mechanics (QM/MM) methods)