A comparative study of galactose oxidase and active site analogs based on QM/MM Car-Parrinello simulations

A parallel study of the radical copper enzyme galactose oxidase (GOase) and a low mol. wt. analog of the active site was performed with dynamic d. functional and mixed quantum-classical calcns. This combined approach enables a direct comparison of the properties of the biomimetic and the natural systems throughout the course of the catalytic reaction. In both cases, five essential forms of the catalytic cycle have been investigated: the resting state in its semi-reduced (catalytically inactive) and its oxidized (catalytically active) form, Asemi and Aox, resp.; a protonated intermediate B; the transition state for the rate-detg. hydrogen abstraction step C, and its product D. For A and B the electronic properties of the biomimetic compd. are qual. very similar to the ones of the natural target. However, in agreement with the exptl. obsd. difference in catalytic activity, the calcd. activation energy for the hydrogen abstraction step is distinctly lower for GOase (16 kcal/mol) than for the mimetic compd. (21 kcal/mol). The enzymic transition state is stabilized by a delocalization of the unpaired spin d. over the sulfur-modified equatorial tyrosine Tyr272, an effect that for geometric reasons is essentially absent in the biomimetic compd. Further differences between the mimic and its natural target concern the structure of the product of the abstraction step, which is characterized by a weakly coordinated aldehyde complex for the latter and a tightly bound linear complex for the former. [on SciFinder (R)]