We have used density functional methods to calculate fully relaxed potential energy curves of the seven lowest electronic states during the binding of O-2 to a realistic model of ferrous deoxyheme. Beyond a Fe-O distance of similar to 2.5 Angstrom, we find a broad crossing region with five electronic states within 15 kJ/mol. The almost parallel surfaces strongly facilitate spin inversion, which is necessary in the reaction of O-2 with heme ( deoxyheme is a quintet and O-2 a triplet, whereas oxyheme is a singlet). Thus, despite a small spin-orbit coupling in heme, the transition probability approaches unity. Using reasonable parameters, we estimate a transition probability of 0.06-1, which is at least 15 times larger than for the nonbiological Fe-O+ system. Spin crossing is anticipated between the singlet ground state of bound oxyheme, the triplet and septet dissociation states, and a quintet intermediate state. The fact that the quintet state is close in energy to the dissociation couple is of biological importance, because it explains how both spin states of O-2 may bind to heme, thereby increasing the overall efficiency of oxygen binding. The activation barrier is estimated to be < 15 kJ/mol based on our results and Mossbauer experiments. Our results indicate that both the activation energy and the spin-transition probability are tuned by the porphyrin as well as by the choice of the proximal heme ligand, which is a histidine in the globins. Together, they may accelerate O-2 binding to iron by &SIM;10(11) compared with the Fe-O+ system. A similar near degeneracy between spin states is observed in a ferric deoxyheme model with the histidine ligand hydrogen bonded to a carboxylate group, i.e. a model of heme peroxidases, which bind H2O2 in this oxidation state.