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Molecular dynamics free energy simulations with a combined quantum mechanical and molecular mechanical (QM/MM) potential are used for modeling the hydrolytic mechanism of a peptide substrate catalyzed by human cathepsin K. The nucleophilic attack by Cys25 thiolate and the proton-transfer reaction from His 162 to the amide nitrogen are highly coupled, whereas a tetrahedral intermediate is formed along the nucleophilic reaction pathway.

An intramolecular proton-transfer mechanism is described for the carbocationic cyclization of farnesyl pyrophosphate (FPP) to (+)-aristolochene catalyzed by aristolochene synthase. The results have shown that the mutations of either residue have led to pronounced generation of aborted cyclization products.

A summary of computational studies of the mechanisms and free energies of selected enzymatic reactions is presented. Computational approaches for enzymatic reactions are highlighted with special emphasis on two key elements affecting the computational accuracy, namely the potential energy function and the statistical mechanical sampling of the enzyme system.

A theoretical study designed to examine the reliability of inferring the transition state structure for an enzyme-catalyzed hydride transfer reaction on the basis of an empirical criterion is presented. Results reveal that the donor carbon at the hydride transfer transition state resembles the reactant state more than the product state, whereas the acceptor carbon is more productlike, which is a symptom of transition state imbalance.