The seminal hypotheses proposed over the years for enzymatic catalysis are scrutinized. The historical record is explored from both biochemical and theoretical perspectives. Particular attention is given to the impact of molecular motions within theprotein on the enzyme's catalytic properties. A case study for the enzyme dihydrofolate reductase provides evidence for coupled networks of predominantly conserved residues that influence the protein structure and motion. Such coupled networks have important implications for the origin and evolution of enzymes, as well as for protein engineering. The fascinating catalytic process executed by enzymes has long remained a mystery. How do enzymes achieve accelerated rates for difficult chemical transformations and exquisite specificity toward substrates distinguished only by their stereochemistry? Here, we review proffered hypotheses, supportive and occasionally counterintuitive experiments, and our current level of understanding or ignorance. As with anysummary, the choice of material reflects our own biases, and doubtless other choices might easily have sufficed. In particular, we look at the question of how molecular motions within the protein's structure may influence the enzyme's catalytic properti
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