Investigating Ferritin Permeability to Metal-Based Drugs through Molecular Dynamics

Abstract In this study, we implemented a workflow based on molecular dynamics (MD) simulations to assess whether gold(I)-containing complexes can traverse the C3 channels of human H ferritin and which energetic barriers were at play in the process. By using two example complexes for which an extensive experimental characterization was already available, we observed that classical MD correctly indicated which one could spontaneously pass through the channel. To quantify the ability of the ferritin nanocage to retain the internalized complex, we estimated, through steered MD and umbrella sampling simulations, the Potential of Mean Force (PMF) along the pathway from the interior to the exterior. The results reveal a steep energetic barrier that hinders the exit of the complex once internalized. In contrast, the second complex encounters steric and electrostatic repulsion, which prevents its internalization. Analysis of protein-complex contacts shows that the successful translocation of the first complex is electrostatically guided through a sequence of transient interactions with Asp/Glu residues lining the pore. The comparison of these two complexes demonstrates that the C3 channel of ferritin only attracts positively charged species and that the nanocage creates a strongly asymmetric energy landscape for charged complexes. This provides a mechanistic explanation for experimental observations of loading in ferritin. Overall, the work demonstrates a computational approach for assessing the permeability of metal-based drugs through ferritin channels and offers molecular insight into channel-mediated transport processes.