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

Area of Science:

• Structural biology
• Molecular dynamics
• Biophysics

Background:

• Human transferrin receptor 1 (TfR1) is key for cellular iron uptake via transferrin (Tf) endocytosis.
• TfR1 is a significant target for anti-cancer strategies, necessitating understanding of its structural dynamics.

Purpose of the Study:

• To model the complete Human transferrin receptor 1 (TfR1) dimer and TfR1-2Tf complex.
• To investigate the conformational dynamics of apo TfR1 and the TfR1-2Tf complex in various environments.
• To identify structural changes upon Tf binding and their implications for therapeutic targeting.

Main Methods:

• Construction of a complete TfR1 dimer model and TfR1-2Tf complex.
• Normal mode analysis and molecular dynamics simulations in solvent and membrane environments.
• Dynamic cross-correlation analysis to assess subdomain coordination.

Main Results:

• Apo TfR1 exhibits high flexibility in the stalk and apical subdomain; Tf binding stabilizes these regions.
• Tf binding limits large tilting motions while preserving essential hinge regions for conformational changes.
• Novel interface residues were identified, enhancing subdomain coordination upon Tf binding.

Conclusions:

• Tf binding stabilizes TfR1 structure, crucial for understanding ligand-induced internalization.
• Findings provide a structural basis for designing TfR1-targeting ligands that preserve functional dynamics.
• Insights support improved drug delivery and receptor inhibition strategies for cancer therapy.