Binding mechanism of disulfide species to ferric hemeproteins: The case of metmyoglobin

The interactions of the heme iron of hemeproteins with sulfide and disulfide compounds are of potential interest as physiological signaling processes. While the interaction with hydrogen sulfide has been described computationally and experimentally, the reaction with disulfide, and specifically the molecular mechanism for ligand binding has not been studied in detail. In this work, we study the association process for disulfane and its conjugate base disulfanide at different pH conditions. Additionally, by means of advanced sampling techniques based on multiple steered molecular dynamics, we provide free energy profiles for ligand migration for both acid/base species, showing a similar behavior to the previously reported for the related H2S/HS? pair. Finally, we studied the ligand interchange reaction (H2O/H2S, HS? and H2O/HSSH, HSS?) by means of hybrid quantum mechanics-molecular mechanics calculations. We show that the anionic species are able to displace more efficiently the H2O bound to the iron, and that the H-bond network in the distal cavity can help the neutral species to perform the reaction. Altogether, we provide a molecular explanation for the experimental information and show that the global association process depends on a fine balance between the migration towards the active site and the ligand interchange reaction.

Automated summary

The interactions between the heme iron of hemeproteins and sulfide and disulfide compounds have potential interest as physiological signaling processes. While the interaction with hydrogen sulfide has been studied computationally and experimentally, the reaction with disulfide and the molecular mechanism for ligand binding have not been thoroughly investigated. In this study, the association process for disulfane and its conjugate base disulfanide at different pH conditions was examined using advanced sampling techniques. The study also investigated the ligand interchange reaction using hybrid quantum mechanics-molecular mechanics calculations and provided a molecular explanation for the experimental information.