The interaction of Fe3+ with blood proteins is very important because it leads to understanding the detrimental effect in biological processes. Molecular dynamic (MD) simulations and quantum chemistry calculations were performed to investigate the complex formation between the human serum albumin (HSA) and Fe3+. MD simulation results predict two binding sites (BSs) of HSA for complex formation including Glu-Arg-Asn-Glu-Cys (BS1) and Lys-Glu-Cys-Cys-Glu-Lys (BS2) amino acids. To investigate the interaction of the corresponding binding sites with Fe3+, quantum chemistry calculations were performed at M06-2X/6-31G(d) level in the water. According to density functional theory calculations, binding constant of Fe3+ to human serum albumin in BS1 (log K = 13.33) is lower than that of BS2 (log K = 18.99), showing higher thermodynamic stability of the HSA-Fe3+ complex in BS2. Natural bond orbital and quantum theory of atoms in molecules analyses demonstrate that the driving force of the complex formation is electrostatic and partially covalent interactions. The results of this research would be valuable to design a suitable iron-chelating agent for the treatment of iron overload.

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