A QM/MM study of the complexes formed by aluminum and iron with serum transferrin at neutral and acidic pH.

Serum transferrin (sTf) transports iron in serum and internalizes in cells via receptor mediated endocytosis. Additionally, sTf has been identified as the predominant aluminum carrier in serum. Some questions remain unclear about the exact mechanism for the metal release or whether the aluminum and iron show the same binding mode during the entire process. In the present work, simulation techniques at quantum and atomic levels have been employed in order to gain access into a molecular level understanding of the metal-bound sTf complex, and to describe the binding of Al(III) and Fe(III) ions to sTf. First, hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations were carried out in order to analyze the dynamics of the aluminum-loaded complex, taking into account the different pH conditions in blood and into the cell. Moreover, the complexes formed by transferrin with Al(III) and Fe(III) were optimized with high level density functional theory (DFT)/MM methods. All these results indicate that the interaction mode of Al(III) and Fe(III) with sTf change upon different pH conditions, and that the coordination of Al(III) and Fe(III) is not equivalent during the metal intake, transport and release processes. Our results emphasize the importance of the pH on the metal binding and release mechanism and suggest that Al(III) can follow the iron pathway to get access into cells, although once there, it may show a different binding mode, leading to a different mechanism for its release.