Binding mechanism of uranyl to transferrin implicated by density functional theory study

Transferrins have been proposed to be responsible for the in vivo transportation of uranyl. In this work, the binding mechanism of uranyl to transferrin has been studied using density functional theory method. Three possible stepwise pathways have been investigated and compared, differing in the sequence of the three residues to bind with uranyl, i.e. Tyr* -> Tyr* -> Asp* (YYD) and Tyr* -> Asp* -> Tyr* (YDY) and Asp* -> Tyr* -> Tyr* (DYY). Compared with the activation energies and the reaction heat of these three possible mechanisms, it is concluded that the YYD pathway is a more plausible description for the binding of uranyl. According to the calculations, the binding process is described as a ligand exchange process assisted by the hydrolysis of uranyl tricarbonate complex, and the role of carbonate ligand which determines the optimal pathway is identified. The QTAIM analysis was used to compare the bond nature of uranyl complexes in its free form and its complex with the amino acid residues. The results are expected to benefit our understanding of the uptake of uranyl by serum transferrins, and have implications on protein engineering and the development of decorporation agents towards improved binding kinetics and thermodynamics of uranyl in a specific pH range