A combined density functional theory and molecular mechanics study of the relationship between the structure of coenzyme B12 and its binding to methylmalonyl-CoA mutase.

A combined density functional theory (DFT) and molecular mechanics (MM) approach was applied to investigate the relationship between the structure of a free coenzyme B12, and bound to methylmalonyl-CoA mutase. It was found that, upon coenzyme binding to apoenzyme, the Co-C bond remains intact, while the C-Naxial bond becomes slightly elongated and labilized. The labilization of the Co-Naxial bond that takes place in coenzyme B12-dependent enzymes is most likely necessary for fine-tuning of the cobalt-nitrogen (axial base) distance. The controlling of this distance is important to inhibit abiological site reaction involving heterolysis of the Co-C bond but is not important for biologically relevant Co-C bond homolysis.