Cobalamins uncovered by modern electronic structure calculations

This review describes how computational methods have contributed to the field of cobalamin chemistry since the start of the new millennium. Cobalamins are cobalt-dependent cofactors that are used for alkyl transfer and radical initiation by several classes of enzymes. Since the entry of modern electronic-structure calculations, in particular density functional methods, the understanding of the molecular mechanism of cobalamins has changed dramatically, going from a dominating view of trans-steric strain effects to a much more complex view involving an arsenal of catalytic strategies. Among these are cis-steric distortions, electrostatic stabilization of radical products, the realization that nucleotide units can serve as polar handles, and the careful design of the active sites, with polar residues in the radical enzymes and non-polar residues in the transferases. Together, these strategies explain the enigmatic Co–C bond cleavage necessary for catalysis by these enzymes.