Quantum Chemical Studies of Proton-Coupled Electron Transfer in Metalloenzymes

In the present review, quantum chemical descriptions of PCET in metalloenzymes have been discussed. The most common type of PCET occurring in enzymes is of the twostep type, where the electron and proton move in separate steps and where the electron and proton have different donors and acceptors. The enzymes discussed here of that type are characterized by the uptake (or release) of electrons and protons from (to) the outside of the enzyme, and this type of long-range electron and proton transfer typically occurs in several steps of PCET. It has been shown how quantum chemical methods can be used to increase the understanding of the mechanisms for these quite complicated types of processes. An important aspect has been how a combination of calculated relative energies and experimental redox potentials can be used to obtain reliable energies for the intermediates. The two enzymes most thoroughly discussed here are cytochrome c oxidase (CcO) and photosystem II (PSII), involving the reduction of molecular oxygen to water, or the reverse reaction of water oxidation with the formation of molecular oxygen. Both these reactions occur in four steps, each comprising the uptake (or release) of one electron and one proton. In the case of CcO, each of the reduction steps is coupled to the translocation of another proton across the entire membrane (in which the enzyme is located). The fact that this pumping occurs without major structural changes or involvement of ATP but is only governed by the electrostatic effects of moving the electrons may make it unique in biology. It was discussed how quantum chemical calculations could be used to elucidate the mechanisms for this complicated coupling of the electron and proton transfer leading to a gating of the protons to the desired place in each step. Another important enzyme discussed is ribonucleotide reductase (RNR), where quantum chemical studies have shown that several different types of PCET occur. In particular, RNR seems to be the most clear case for which hydrogen-atom transfer (HAT) is involved in long-range radical transfer, with the electron and proton being transferred between the same donor and acceptor molecule (two tyrosines or a cysteine and a tyrosine). The QM models used for quantum chemical studies of PCET processes have grown over the past two decades from about 20 atoms to the present 250 atoms. Increasing the size of the models leads to additional difficulties, such as the presence of many local minima, which is at the present stage a major challenge in the modeling. It can be expected that the growing experience with large models will lead to still better treatments of this local minima problem in the future. However, it should be stressed that very large models are not needed, not even desired, for all types of problems. It can be predicted that also in the future the main features of most PCET mechanisms will be elucidated using rather small models. Extended models can then be used to make the mechanisms found with the small models more convincing. © 2010 American Chemical Society.