According to previous quantum mechanics/molecular mechanics (QM/MM) studies, camphor hydroxylation in cytochrome P450 is catalysed by a single water molecule which lowers the computed B3LYP/CHARMM barrier by about 4 kcal mol(-1). Gas-phase B3LYP model studies for a variety of different substrates show the generality of this effect. Its origin is an electrostatic enhancement of hydrogen bonding in the transition state for hydrogen abstraction. Attempts are made to correlate the slight variations in the calculated barrier lowerings with substrate properties. Individual water molecules also have a decisive influence on other reactions in cytochrome P450cam, for instance, on the relative propensity for coupling and uncoupling upon protonation of Compound 0 in the wild-type enzyme and its mutants. These and other examples are reviewed briefly. Finally, we address some methodological issues on how to handle the possible involvement of water molecules in biocatalysis at the QM/MM level.
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