Ghanbari Z, Housaindokht M R, Bozorgmehr M R, Izadyar M
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
J Mol Graph Model. 2017 Nov;78:176-186. doi: 10.1016/j.jmgm.2017.10.013. Epub 2017 Oct 18.
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 residuesof the transferrin structure.
阴离子在转铁蛋白化学中的作用突出了转铁蛋白家族中阴离子结合位点的重要性。作为协同阴离子的碳酸根是转铁蛋白结合铁所必需的阴离子，而非协同阴离子并不作为促进铁结合的协同阴离子，而是影响铁的结合和释放。关于协同阴离子和非协同阴离子功能之间的差异，仍有一些问题尚不清楚。在本研究中，采用分子动力学模拟技术，以便在分子水平上了解人血清转铁蛋白在协同阴离子和非协同阴离子结合过程中的铁结合位点。为此，进行了比较分析以说明观察到的变化。除了比较协同阴离子和非协同阴离子之外，还研究了两种协同阴离子碳酸根和草酸根之间的结构差异。同时，对转铁蛋白结构的开放（脱铁）、部分闭合（碳酸根）和完全闭合（碳酸根 - 铁）形式的模拟允许直接比较这三种状态的铁结合位点。基于结果，协同阴离子形成高亲和力结合位点，而非协同阴离子的作用类似于转铁蛋白结构的脱铁状态并改变结合位点的适当构象。为了作为协同阴离子并形成高亲和力结合位点，阴离子立体化学和相互作用必须能够实现类似碳酸根的构型。碳酸根复合物显示出最高的结合亲和力，并且静电能是协同阴离子 - 转铁蛋白相互作用的主要有利贡献因素。作为协同阴离子的碳酸根和草酸根复合物有许多共同特征，转铁蛋白结构没有显著变化。仅结合位点附近的残基根据协同阴离子是碳酸根还是草酸根而显示出略有不同的构象。最后，结果表明，在碳酸根和铁结合过程中，ASP63、GLY65和HIS249残基具有最大位移。ASP63和HIS249是与铁配位的残基，而GLY65位于转铁蛋白结构的第二壳层残基中。
