Development and application of efficient and accurate methods for computational enzymology

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Computational enzymology is the study of enzymes and enzymatic reactions using computer simulations. It aims primarily at predicting the structure and energy of the short-lived states along an enzymatic reaction, and at connecting them into an atomically-detailed picture. Because these short-lived states are usually not accessible through experimental techniques, computational enzymology can provide new insights into what makes an enzyme work or into how the activity of an enzyme can be enhanced or inhibited.***The long-term objectives of our research are to (1) develop methods for computational enzymology that are accurate enough to reveal the mechanism of complex enzymatic reactions, yet efficient enough to simulate the catalytic effects of large-scale protein motion, and (2) use those methods to design new enzymes and new drugs.***We are particularly interested in developing computational methods for metalloenzymes, which contain one or many metal cofactors at their reaction sites (zinc, calcium, magnesium, iron, etc.) and are prime targets for medical and industrial applications. Zinc hydrolases, for instance, are involved in numerous biological functions such as blood pressure regulation, tissue repair, and bacterial resistance to antibiotics. Although about half of all known proteins contain at least one metal atom, no method is currently available to efficiently and reliably simulate chemical reactions at metal-binding sites.**