A DFT-informed parameterization strategy for accurate modeling of his-mediated local interactions in ferritin systems

Ferritin is a widely studied protein with broad applications in nanotechnology and biomolecular systems, for which molecular dynamics (MD) simulations are commonly employed to investigate structural and interaction behaviors. However, default force fields often fail to accurately capture local interactions, particularly in genetically modified variants. In this study, we developed a DFT-informed force field for human heavy-chain ferritin (HFn) and its genetically modified variant, 8His-HFn, to improve the description of the His-mediated local interactions. A simplified His-small molecule model was constructed, using CO₂ as a representative probe, to generate reference energy profiles via density functional theory (DFT) calculations. The Lennard-Jones parameters governing these local interactions were optimized using the GULP package, resulting in substantially improved agreement with the DFT energy profiles, particularly in the short-range interaction region. Molecular dynamics simulations of both simplified model systems and hydrated 8His-HFn systems demonstrate that the reparameterized force field provides a more accurate description of local interactions while preserving the structural integrity of the ferritin nanocage. Overall, this work establishes a transferable parameterization strategy for describing His-mediated local interactions and provides a practical route for incorporating quantum-mechanical information into large-scale biomolecular simulations of ferritin-based systems.