Molecular mechanics studies of coenzyme B12 complexes with constrained CoN(axial-base) bond lengths: introduction of the universal force field (UFF) to coenzyme B12 chemistry and its use to probe the plausibility of an axial-base-induced, ground-state co

The universal force field (UFF) is used to minimize a series of cobalamins to (i) test the applicability of UFF to model unstrained cobalamin structures in comparison with the literature force field MM2′, a force field parameterized using a set of 19 cobalamin X-ray crystal structures, and (ii) to probe the steric-based, ground-state corrin butterfly effect, a literature hypothesis aimed at explaining the observed 1012 enzymic acceleration of adenosylcobalamin (AdoCbl) CoC bond homolysis. The results obtained show that UFF is at least as good as MM2′ in modeling the five cobalamins which were originally used to test the accuracy of MM2′. Next, by using UFF to constrain the CoN(bzm) bond length in adenosylcobalamin (AdoCbl) to bond lengths ranging from 4.5 to 1.44 Å, the putative axial-base-induced corrin butterfly conformation effect was modeled. The results show that while a short CoN(bzm) bond length does lengthen the CoC bond and increase the CoCC bond angle, the maximum magnitude of the predicted distortions appears, at least when considering steric effects alone, to be at most ∼1/3 that needed to accomplish the observed CoC bond homolysis acceleration. Equivalent results were obtained in analogous studies of base-free adenosylcobinamide (AdoCbi+) in the presence of an exogenous N-methylimidazole base, [AdoCbi·N-MeIm]+. Overall, literature precedent, and now UFF molecular mechanics, all provide evidence against a solely axial-base-driven, sterically-induced corrin butterfly conformation effect as the dominant mechanism in the enzymic acceleration of AdoCbl CoC bond homolysis. Serious consideration must now be given to a combination of effects: an enzyme-induced rack mechanism (which can contain an enzyme-induced corrin butterfly conformational effect), and a coupling of Co⋯C cleavage, substrate or cysteine S⋯H bond cleavage, and Ado⋯H bond formation steps.