Enzymes are biological molecules that accelerate chemical reactions. They are central to the existence of life. Since the discovery of enzymes just over a century ago, we have witnessed an explosion in our understanding of enzyme catalysis, leading to a more detailed appreciation of how they work. A key breakthrough came from understanding how enzymes surmount the potential-energy barrier that separates reactants from products. The genetic engineering revolution has provided tools for dissecting enzyme structure and enabling design of novel function. Despite the huge efforts to redesign enzyme molecules for specific applications, progress in this area has been generally disappointing. This stems from our limited understanding of the subtleties by which enzymes enhance reaction rates. Based on current dogma, the vast majority of studies have concentrated on understanding how enzymes facilitate passage of the reaction over a static potential-energy barrier. However, recent studies have revealed that passage through, rather than over, the barrier can occur. These studies reveal that quantum mechanical phenomena, driven by protein dynamics, can play a pivotal role in enzyme action. The new millennium will witness a flurry of activity directed at understanding the role of quantum mechanics and protein motion in enzyme action. We discuss these new developments and how they will guide enzymology into the new millennium.
