Many globins convert (NO)-N-center dot to innocuous NO3- through their nitric oxide dioxygenase (NOD) activity. Mycobacterium tuberculosis fights the oxidative and nitrosative stress imposed by its host (the toxic effects of O-2(center dot-) and (NO)-N-center dot species and their OONO- and (NO2)-N-center dot derivatives) through the action of truncated hemoglobin N (trHbN), which catalyzes the NOD reaction with one of the highest rates among globins. The general NOD mechanism comprises the following steps: binding of O-2 to the heme, diffusion of (NO)-N-center dot into the heme pocket and formation of peroxynitrite (OONO-), isomerization of OONO-, and release of NO3-. Using quantum mechanics/molecular mechanics free-energy calculations, we show that the NOD reaction in trHbN follows a mechanism in which heme-bound OONO- undergoes homolytic cleavage to give Fe-IV=O-2(-) and the (NO2)-N-center dot radical but that these potentially harmful intermediates are short-lived and caged by the heme pocket residues. In particular, the simulations show that Tyr33(B10) side chain is shielded from Fe-IV=O-2(-) and (NO2)-N-center dot (and protected from irreversible oxidation and nitration) by forming stable hydrogen bonds with GIn58(E11) side chain and Leu54(E7) backbone. Aromatic residues Phe46(CD1), Phe32(B9), and Tyr33(B10) promote NO3- dissociation via C-H center dot center dot center dot O bonding and provide stabilizing interactions for the anion along its egress route.