Binding Energy and Enzymatic Catalysis

For nearly 100 years, the extraordinary catalytic power of enzymes has fascinated biochemists (1). In a recent article in this Journal, Splittgerber (2) analyzed several ofthe factors by which enzymes are thought to effect catalysis, including proximity and orientation effects, substrate strain, acidbase catalysis, and nucleophilic catalysis. Here we will discuss the fundamental role that the favorable free energy of binding of the rate-determining transition state plays in catalysis and will review the principle that all of the catalytic factors mentioned above, as well as numerous others (3), are realized by the use of this binding energy. At the most basic level, enthalpically favorable binding interactions between an enzyme and the transition state of the reaction being catalyzed-regardless of the nature of these interactionslower the free energy of activation and thus lead to catalysis. Indeed, as Jencks has recently reiterated (4), transition state stabilization "is required by the definitions of catalysis and of the transition state." As early as 1930, Haldane (5) recognized the importance of binding energy in catalysis when he suggested that an enzyme acts by distorting the structures of the substrates toward those of the products. Eighteen years later, Pauling, in a seminal statement (6), modified Haldane's suggestion and postulated that "enzymes are molecules that are complementary in structure to the [transition states] of the reactions that they catalyze." In 1975, Jencks (7), concisely defined binding energy, calling it