High-accuracy computation of reaction barriers in enzymes.

With the advent of combined quantum mechanics / molecular mechanics (QM/MM) methods, enzymatic reactions have become accessible to theoretical modeling in recent years. QM/MM calculations on enzymes have generally been restricted to semiempirical or density functional QM treatments, which are realistic but of limited accuracy and cannot be improved in a systematic manner. In this work it has for the first time been possible to apply high-level coupled-cluster ab initio electronic structure methods to enzymatic catalysis, in a QM/MM framework. Excellent agreement is obtained between the computed and the experimentally determined activation barriers for two quite different enzymatic reactions, a Claisen rearrangement in chorismate mutase and an electrophilic aromatic substitution in parahydroxybenzoate hydroxylase. This agreement between experimental and converged theoretical results has broader implications concerning the role of specific dynamic effects in enzyme catalysis that are currently under debate: at least for the two enzymes studied here, such dynamic effects must be small since standard transition state theory describes the reactivity quantitatively.