Conformational dynamics study of TfR1 upon transferrin binding via NMA and MD simulations

The Human transferrin receptor 1 (TfR1) mediates cellular iron uptake via clathrin-mediated endocytosis of transferrin (Tf) and is an important therapeutic target, particularly in anti-cancer strategies. Understanding its structural dynamics is crucial to avoid disrupting ligand-induced internalization. In this study, we constructed a complete model of the TfR1 dimer and docked two Tf structures to form the TfR1-2Tf complex. Conformational dynamics of apo TfR1 and the TfR1-2Tf complex were investigated using normal mode analysis and molecular dynamics simulations, including solvent and membrane environments. In apo TfR1, the molecular stalk and apical subdomain were highly flexible, whereas the helical and protease-like subdomains displayed moderate mobility. Tf binding stabilizes the stalk and upper helical subdomain, limiting large tilting motions, while preserving hinge regions necessary for conformational changes. Dynamic cross-correlation analysis showed that Tf binding also enhances coordination between subdomains. Novel interface residues mediating interactions between the Tf N-lobes and the TfR1 stalk were identified. These findings provide a valuable structural basis for rational ligand design targeting TfR1 without disrupting its functional dynamics, offering insights for improved drug delivery and receptor inhibition strategies. • A full-length transferrin receptor model, validated against crystal structures • Molecular dynamics reveals domain motions and hinge flexibility of the receptor • Transferrin binding reduces stalk flexibility and enhances inter-domain coordination • Identification of new key TfR1-Tf interface residues by docking and energy analysis • Binding free energy decomposition confirms electrostatic complex stabilization