Protein motions and the activation of the CH bond catalyzed by dihydrofolate reductase.

The role of protein motions in enzymatic CH→C transfer is an area of great contemporary debate. An effective tool in probing such a role is the temperature dependence of the intrinsic kinetic isotope effects for the enzyme-catalyzed reaction. The outcome of those experiments is interpreted within the context of phenomenological Marcus-like models of hydrogen tunneling. The current review focuses on recent studies of dihydrofolate reductase (DHFR) and how the role of protein motions in the catalyzed reaction has been demonstrated. The motions in DHFR are controlled by local effects of active site residues, global effects involving remote residues across the enzyme and appear to be preserved during the evolution of the enzyme from bacteria to human.