Coordination of inorganic disulfide species to ferric N-acetyl microperoxidase 11

The interest in chemical interactions between inorganic sulfur species and heme compounds has grown significantly in recent years due to their physiological relevance. The model system ferric N-acetyl microperoxidase 11 (NAcMP11Fe^III) enables the exploration of the mechanistic aspects of the interaction between the ferric heme group and binding sulfur ligands, without the constraints imposed by a protein matrix and the stabilizing effects of distal amino acids. In this study, we investigated the coordination of disulfane (HSSH) and its conjugate base hydrodisulfide (HSS^-) to NAcMP11Fe^III. Kinetic estimations of the binding constant retrieved a pH-independent k_on= (1.5 ± 0.7) x10⁵ M^-1s^-1, for 6.4 ≤ pH ≤ 7.2, and a similar value for the intrinsic constant for HSS^-, the predominant species. To obtain a molecular description of the binding process, we resorted to two complementary theoretical approaches. Firstly, using multiple steered molecular dynamics, we calculated the free energy profiles for the migration of the neutral species HSSH and the monoanionic HSS^-, and also for the siblings hydrogen sulfide, H₂S, and hydrosulfide, HS^-. Our results reveal that both neutral and anionic species can achieve the distal cavity, as expected considering the highly solvent exposed heme group in NAcMP11Fe^III. Secondly, we explored the ligand-exchange reaction using a combination of nudged elastic band (NEB) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations, which suggest that the monoanionic species can displace the water molecule coordinated to the heme iron more efficiently than the neutral ones. Altogether, our results provide a molecular description of the ligand binding process of these sulfur species to ferric heme proteins.