We review the state of the art of combined quantum mechanical/molecular mechanical calculations on enzyme systems and carry out a further analysis of the role of preorganization effects on enzyme catalysis. On the basis of our calculations, the free energy cost of aligning the functional groups for catalysis (the preorganization free energy) is responsible for a substantial fraction of the 10(11)-10(13) faster rates of the enzyme-catalyzed reactions for trypsin and catechol O-methyltransferase compared to analogous reference reactions in aqueous solution. Although the preorganization free energy contains a large entropic contribution, entropy effects on going from the enzyme-substrate noncovalent complex to the transition state for the reaction are expected to be generally small and not very different in enzyme and in solution. We attempt to give a critical analysis of both our approach and that of Warshel to elucidating the reason for large enzymatic rate enhancements.