Light-Induced Activation of Organo-Metallic Co-C Bond in MeCbl-Dependent Methionine Synthase- QM/MM Study

Abstract

Methylcobalamin (MeCbl)-dependent enzyme methionine synthase (MetH), plays a critical role in the catalysis of methyl group transfer from methyltetrahydrofolate to homocysteine. It often performs a side reaction to generate cob (II)alamin through photolysis of organometallic Co-C bond. A hybrid QM/MM method (DFT/MM and TD-DFT/MM) has been performed to explore the photochemistry of MeCbl-bound MetH. The manifold of low-lying excited states and corresponding potential energy surface (PES) of electronically excited S1 state has been constructed as a function of axial bond lengths to elucidate the mechanism of photoinduced activation of Co-C bond inside enzyme to investigate the photolytic properties of MeCbl-bound MetH. The analysis of S1 PES has revealed that the two different electronic states, namely metal-to-ligand charge transfer (MLCT) and the ligand field (LF), of S1 PES are relevant to the photodissociation of Co-C bond. There are two possible pathways identified, Path A and Path B, that connect the MLCT to LF state that represent possible photodissociation mechanisms. In the case of MetH, one possible photodissociation pathway (Path B) was identified based on the energetics of MLCT and LF states.The energetically accessible Path B involves initial the detachment of Co-NIm followed by a displacement of the Co-C bond prior the formation of cob(II)alamin / CH3 radical pair (RP). The photochemical data of base-on MeCbl was compared with the computed result of MeCbl-bound MetH to understand the effect of enzymatic environment on the photolytic properties of MeCbl. In compare to MeCbl in solution, the LF state is energetically higher in energy inside the enzyme which makes it easier to form RP for isolated cofactor in solution. Therefore the enzymatic environment has played a role in the destabilization of the LF state which impede the photolysis of MeCbl-bound MetH.