We present here an energetic and atomistic description of how
D-ornithine 4,5-aminomutase (OAM), an
adenosylcobalamin (
AdoCbl;
coenzyme B(12))-dependent
isomerase, employs a large-scale protein domain conformational change to orchestrate the homolytic
rupture of the Co-C bond. Our results suggest that in going from the open form (catalytically inactive) to the closed form (catalytically active), the Rossmann domain of OAM effectively approaches the active site as a rigid body. It undergoes a combination of a ~52° rotation and a ~14 Å translation to bring
AdoCbl-initially positioned ~25 Å away-into the active-site cavity. This process is coupled to repositioning of the
Ado moiety of
AdoCbl from the eastern conformation to the northern conformation. Combined quantum mechanics and molecular mechanics calculations further indicate that in the open form, the
protein environment does not impact significantly on the Co-C bond homolytic
rupture, rendering it unusually stable, and thus catalytically inactive. Upon formation of the closed form, the Co-C bond is activated through the synergy of steric and electrostatic effects arising from tighter interactions with the surrounding
enzyme. The more pronounced effect of the
protein in the closed form gives rise to an elongated Co-C bond (by 0.03 Å), puckering of the
ribose and increased "strain" energy on the
Ado group and to a lesser extent the
corrin ring. Our computational studies reveal novel strategies employed by
AdoCbl-dependent
enzymes in the control of radical catalysis.