Modeling the Reactions Catalyzed by Coenzyme B₁₂ Dependent Enzymes: Accuracy and Cost-Quality Balance

The reactions catalyzed by coenzyme B₁₂ dependent enzymes are formally initiated by the homolytic cleavage of a carbon-cobalt bond and a subsequent or concerted H-atom-transfer reaction. A reasonable model chemistry for describing those reactions should, therefore, account for an accurate description of both reactions. The inherent limitation due to the necessary system size renders the coenzyme B₁₂ system a suitable candidate for DFT or hybrid QM/MM methods; however, the accurate description of both homolytic Co-C cleavage and H-atom-transfer reactions within this framework is challenging and can lead to controversial results with varying accuracy. We present an assessment study of 16 common density functionals applied to prototypical model systems for both reactions. H-abstraction reactions were modeled on the basis of four reference reactions designed to resemble a broad range of coenzyme B₁₂ reactions. The Co-C cleavage reaction is treated by an ONIOM(QM/MM) setup that is in excellent agreement with solution-phase experimental data and is as accurate as full DFT calculations on the complete model system. We find that the meta-GGAs TPSS-D3 and M06L-D3 and the meta-hybrid M06-D3 give the best overall performance with MUEs for both types of reactions below 10 kJ mol^-1. Our recommended model chemistry allows for a fast and accurate description of coenzyme B₁₂ chemistry that is readily applicable to study the reactions in an enzymatic framework.