An integrated model for enzyme catalysis emerges from studies of hydrogen tunneling.

The origins of the enormous rate accelerations brought about by enzymes are discussed. The focus is on enzymatic C-H activation, which has been shown to take place via tunneling. Four enzyme systems illustrate the impact of site-specific mutagenesis, changes in temperature or changes in protein solvation on the tunneling properties. A model emerges in which conformational sampling is required to access a subset of protein conformers where the H-donor and acceptor undergo a close approach. The evidence for an inverse relationship between protein flexibility and active site compression is likely to extend to all classes of enzyme catalysts.