The most common type of reaction carried out by non-heme iron enzymes is C-H hydroxylation, which is crucial in lipid metabolism and biosynthesis of antibiotics such as vancomycin, fosfomycin, and carbapenem. The active site of the aKG-dependent non-heme iron hydroxylases consists of the canonical 2-His-1-carboxylate facial triad bound to an Fe center where the carboxylate is usually Glu/Asp. Ferryl intermediates formed during the catalytic cycle of these enzymes are highly reactive, which makes them hard to characterize by experimental techniques such as crystallography and spectroscopy. An experimental approach to structurally characterize these fleeting ferryl intermediates frequently invoked in C-H activation is to replace them with more inert V-based mimics, which has been carried out for non-heme iron oxygenases and hydroxylases. Furthermore, study of vanadyl mimics has been carried out in combination with the spectroscopic guidance derived from HYSCORE spectroscopy. However, this approach is not without limitations, as demonstrated in a prior computational study of vanadyl mimics of non-heme iron halogenases. Given the differences in the electronic structures of Fe and V, and the bond lengths of Fe-His and V-His bonds in the active site intermediates, computational studies are necessary to provide insights into shortcomings of using vanadyl mimics to study ferryl intermediates.