Mechanistic insights into metal ions transit through threefold ferritin channel

Background: The mechanism of how the hydrophilic threefold channel (C3) of ferritin nanocages facilitates diffusion of diverse metal ions into the internal cavity remains poorly explored. Methods: Computational modeling and free energy estimations were carried out on R. catesbeiana H´ ferritin. Transit features and associated energetics for Fe 2+ , Mg 2+ , Zn 2+ ions through the C3 channel have been examined. Results: We highlight that iron conduction requires the involvement of two Fe 2+ ions in the channel. In such doubly occupied configuration, as observed in X-ray structures, Fe 2+ is displaced from the internal site (stabilized by D127) at lower energetic cost. Moreover, comparison of Fe 2+ , Mg 2+ and Zn 2+ transit features shows that E130 geometric constriction provides not only an electrostatic anchor to the incoming ions but also differentially influence their diffusion kinetics. Conclusions: Overall, the study provides insights into Fe 2+ entry mechanism and characteristic features of metal-protein interactions that influence the metal ions passage. The dynamics data suggest that E130 may act as a metal selectivity gate. This implicates an ion-specific entry mechanism through the channel with the distinct diffusion kinetics being the discriminating factor. General Significance: Ferritin nanocages not only act as biological iron reservoirs but also have gained importance in material science as template scaffolds for synthesizing metal nanoparticles. This study provides mechanistic understanding on the conduction of different metal ions through the channel.