NO–Imi–H2O complexes can be used as models to investigate the interactions of histidine with nitric oxide and water in biological systems like myoglobin. We discuss here the water–imidazole, water–nitric oxide dimers and the trimolecular complexes of nitric oxide with water and imidazole from the donor–acceptor point of view using the natural bond orbitals and localized molecular orbital energy decomposition analysis schemes. The comparison between trimolecular and bimolecular complexes shows that in general, the stabilization energies are more sensitive to changes in the interactions of imidazole with water than to changes in the interactions with nitric oxide. The effect of imidazole ring protonation on the geometry and stabilization of the complexes is also investigated. We found that cooperative effects are more relevant in charged complexes and planar structures than in neutral species and nonplanar complexes. The driving forces governing the interactions between open and closed shell systems are also discussed with special emphasis on the role of lone pairs and unpaired electrons.