Lead Chief Investigator

Peter L Cummins Genome Biology, JCSMR, Australian National University

Project Title

Quantum Chemical Studies of Enzymic Reactions

Brief Description for General Publications

An understanding of the mechanisms by which protein and solvent environments influence the stability of reactants, products and transition states in biologically significant reactions is important and has a number of applications, for example, in the rational design of enzyme inhibitors as possible drugs and enzyme re-engineering. Computational methods may provide useful insights into these mechanisms. Both quantum mechanical (QM) and molecular mechanical (MM) methods are useful for the computational study of enzymic reaction mechanisms. Since enzymes are solvated systems, it is often necessary to adopt hybrid models for the interaction of the reaction centre (QM) with both the surrounding protein and solvent medium (MM). We can in principle use hybrid QM/MM methods and molecular dynamics (MD) simulation techniques to obtain local free energy minima (reactant and product states) and transition states with respect to a suitably chosen set of reaction coordinates, but the approximations inherent in these methods can produce unreliable results. Given access to "state of the art" parallel computers, calculations can now be routinely perfomed on fragment models involving hundreds of QM atoms. This project focuses primarily on assessing the utility such QM calculations for exploring the energetics of reaction pathways in enzymes.