The role of the anions in transferrin chemistry highlights the importance of the anion binding site in transferrin family. A synergistic anion as carbonate is an anion that is required for iron binding by transferrin while non-synergistic anions do not act as the synergistic anions to promote iron binding, but affect the iron binding and release. Some questions remain unclear about the difference between synergistic and non-synergistic anion functions. In the present work, molecular dynamic simulation techniques were employed in order to gain access into a molecular level understanding of the iron binding site of the human serum transferrin during the synergistic and non-synergistic anion binding. For this purpose, a comparative analysis was performed to illustrate the observed changes. In addition to the comparison between the synergistic and non-synergistic anions, structural differences between two synergistic anions, Carbonate and Oxalate were studied. Meanwhile, the simulation of the open (Apo), partially closed (Carbonate) and fully closed (Carbonate-Fe) forms of the transferrin structure allows a direct comparison between the iron binding site of these three states.On the basis of results, synergistic anions form high affinity binding site, while non-synergistic anions act like Apo state of the transferrin structure and change the proper conformation of the binding site. In order to act as a synergistic anion and form high affinity binding site, anion stereochemistry and interactions must be able to achieve a Carbonate-like configuration. Carbonate complex showed the highest binding affinity and electrostatic energy is the major favorable contributor to synergistic anion-transferrin interaction. Carbonate and Oxalatecomplexes as synergistic anions have many features in common, without a significant change in the transferrin structure. Only the residues in the vicinity of the binding site showed a little different conformation depending on whether the synergistic anion is Carbonate orOxalate.Finally, the results show thatASP63, GLY65 and HIS249 residues have the maximum displacement during the Carbonate and iron binding. ASP63 and HIS249 are the residues, which are coordinated to the iron and GLY65 is in the second shell residues of the transferrin structure.

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