Product stabilization in the enzymatic activation of coenzyme B12: a molecular modeling study

Earlier calculations of the possible involvement of the axial base of coenzyme B12 in the mechanism of its enzymatic activation for Co–C bond homolysis led to the conclusion that classical ground state ‘mechanochemical triggering’, in which compression of the axial Co–N bond leads to destabilization of the Co–C bond in the ground state, was unlikely to provide significant catalytic power, but that so-called ‘transition state mechanochemical triggering’, in which such bond compression electronically stabilizes the transition state by improving the Co–N overlap, was a viable candidate for the mechanism of coenzyme activation. However, it is now clear that Co–C bond homolysis of coenzyme B12 at an enzyme active site is a simple bond dissociation reaction, the reaction coordinate diagram has no maximum, and there is no transition state. Consequently, the reaction can be accelerated only by destabilization of the reactant or stabilization of the homolysis products. In the current work, the possibility of stabilization of the cob(II)alamin product by compression of the axial Co–N bond to improve orbital overlap is addressed by molecular modeling and molecular orbital calculations. Two different semi-empirical open-shell calculations give differing results, so that the feasibility of such product stabilization cannot be answered unequivocally by such calculations.