Faculty of Engineering and Natural Sciences, Sabancı University, Orhanlı 34956, Tuzla, Istanbul, Turkey.
Metallomics. 2017 Nov 15;9(11):1513-1533. doi: 10.1039/c7mt00216e.
With the advances in three-dimensional structure determination techniques, high quality structures of the iron transport proteins transferrin and the bacterial ferric binding protein (FbpA) have been deposited in the past decade. These are proteins of relatively large size, and developments in hardware and software have only recently made it possible to study their dynamics using standard computational resources. We review computational techniques towards understanding the equilibrium and kinetic properties of iron transport proteins under different environmental conditions. At the level of detail that requires quantum chemical treatments, the octahedral geometry around iron has been scrutinized and it has been established that the iron coordinating tyrosines are in an unusual deprotonated state. At the atomistic level, both the N-lobe and the full bilobal structure of transferrin have been studied under varying conditions of pH, ionic strength and binding of other metal ions by molecular dynamics (MD) simulations. These studies have allowed questions to be answered, among others, on the function of second shell residues in iron release, the role of synergistic anions in preparing the active site for iron binding, and the differences between the kinetics of the N- and the C-lobe. MD simulations on FbpA have led to the detailed observation of the binding kinetics of phosphate to the apo form, and to the conformational preferences of the holo form under conditions mimicking the environmental niches provided by the periplasmic space. To study the dynamics of these proteins with their receptors, one must resort to coarse-grained methodologies, since these systems are prohibitively large for atomistic simulations. A study of the complex of human transferrin (hTf) with its pathogenic receptor by such methods has revealed a potential mechanistic explanation for the defense mechanism that arises in evolutionary warfare. Meanwhile, the motions in the transferrin receptor bound hTf have been shown to disfavor apo hTf dissociation, explaining why the two proteins remain in complex during the recycling process from the endosome to the cell surface. Open problems and possible technological applications related to metal ion binding-release in iron transport proteins that may be handled by hybrid use of quantum mechanical, MD and coarse-grained approaches are discussed.
随着三维结构测定技术的进步，过去十年中已经有大量转铁蛋白和细菌铁结合蛋白（FbpA）的高质量结构被存入数据库。这些都是相对较大的蛋白质，硬件和软件的发展直到最近才使得使用标准计算资源研究它们的动力学成为可能。我们回顾了理解不同环境条件下铁转运蛋白的平衡和动力学特性的计算技术。在需要量子化学处理的细节水平上，已经仔细研究了铁周围的八面体几何形状，并已确定铁配位的酪氨酸处于异常去质子化状态。在原子水平上，通过分子动力学（MD）模拟，在不同 pH 值、离子强度和其他金属离子结合条件下，研究了转铁蛋白的 N-结构域和完整双叶结构。这些研究回答了一些问题，例如，第二壳层残基在铁释放中的作用、协同阴离子在为铁结合准备活性位点方面的作用以及 N-结构域和 C-结构域的动力学之间的差异。对 FbpA 的 MD 模拟导致了对apo 形式与磷酸盐结合的结合动力学的详细观察，以及在模拟周质空间提供的环境小生境条件下的 holo 形式的构象偏好。为了研究这些蛋白质与其受体的动力学，人们必须求助于粗粒度的方法，因为这些系统对于原子模拟来说太大了。通过这种方法研究人转铁蛋白（hTf）与其致病受体的复合物，揭示了进化战争中出现的防御机制的潜在机械解释。与此同时，在转铁蛋白受体结合的 hTf 中的运动不利于 apo hTf 的解离，解释了为什么在从内体到细胞表面的再循环过程中，这两种蛋白质仍保持复合物状态。讨论了可能通过量子力学、MD 和粗粒度方法的混合使用来处理的与铁转运蛋白中的金属离子结合-释放相关的未解决问题和可能的技术应用。
