Perspective on “The energetics of enzymatic reactions”
The origin of the catalytic power of enzymes has been one of the most important open problems in molecular biology. Our early computer modeling studies [Warshel A, Levitt M (1976) J Mol Biol 103: 227 indicated that electrostatic effects give the largest contributions to enzyme catalysis; however, it was not clear how enzymes can provide more electrostatic stabilization to their transition states than water does. This fundamental problem has been solved by the title paper. The paper pointed out that in reactions in water the solvent must pay significant electrostatic energy for orienting its permanent dipoles toward the transition states. It was then demonstrated that in enzymes the active site dipoles are already partially preoriented in the optimum direction and so much less electrostatic energy is lost in the reorganization process. It was further demonstrated that ion pairs and related transition states are less stable in water than in preoriented dipolar environments in general and in the active sites of real enzymes in particular. Thus, it was concluded that enzymes stabilize their transition states by preoriented dipoles and that the catalytic energy is already stored in the preorientation of these dipoles during the folding process rather than in the enzyme substrate interaction.
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