Billions of years of evolution have led to enzymes, the most efficient, specific and selective catalysts known. Due to the complexity and the electronic requirements of some biochemical reactions, nearly half of all enzymes found in Nature present transition metals (TM) as essential cofactors for catalysis. But not all chemical processes have a natural enzyme that catalyzes them.<br/>Very recently, the groups of Arnold and Hartwig, among others, have expanded the repertoire of metalloenzyme-catalyzed reactions towards new synthetically important reactions not observed in Nature. One of the most impressive achievements is the engineering of artificial metalloenzymes for catalyzing transfers of carbenes, nitrenes and oxenes for functionalizing olefins and C-H bonds.<br/><br/>In collaboration with the groups of Arnold and Hartwig, we have studied two related systems: (1) the activation of the iron-heme P450-BM3 cytochrome towards the carbene insertion into olefins by the modification of the axial ligand of the heme cofactor; and (2) the C-H carbene insertion catalyzed by abiological Ir-containing heme P450.<br/>Using a combination of density functional theory (DFT) quantum mechanics calculations and molecular dynamics (MD) simulations, our computations describe the reaction mechanisms that are taking place. In agreement with the experiments, our results show that the rate-limiting step in all studied cases corresponds to the carbenoid formation, while the carbene insertions occur through lower in energy transition states. Finally, our MD simulations point out how protein environment and new introduced mutations dictate the stereoselectivity in the C-H carbene insertion catalyzed by Ir-heme P450, giving a rational point of view that sets the stage for further protein engineering.

Origins of the catalytic proficiency of cytochrome-based artificial metalloenzymes

253rd National Meeting (2017)

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