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Computational approaches for deciphering equilibrium and kinetic properties of iron transport proteins
Metallomics ( IF 3.4 ) Pub Date : 2017-09-19 00:00:00 , DOI: 10.1039/c7mt00216e
H. Abdizadeh 1, 2, 3, 4 , A. R. Atilgan 1, 2, 3, 4 , C. Atilgan 1, 2, 3, 4 , B. Dedeoglu 1, 2, 3, 4
Affiliation  

With the advances in three-dimensional structure determination techniques, high quality structures of 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 on standard computational resources. We review computational techniques towards understanding the equilibrium and kinetic properties of iron transport proteins under different environmental conditions. At the detail that requires quantum chemical treatments, the octahedral geometry around iron has been scrutinized and that the iron coordinating tyrosines are in an unusual deprotonated state has been established. At the atomistic detail, 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 answering questions, among others, on the function of second shell residues in iron release, the role of synergistic anions on 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 in 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. 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 the 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.

中文翻译:

破译铁转运蛋白平衡和动力学性质的计算方法

随着三维结构测定技术的进步,在过去十年中已经沉积了铁转运蛋白转铁蛋白和细菌铁结合蛋白(FbpA)的高质量结构。这些是相对大的蛋白质,并且硬件和软件的发展直到最近才使人们有可能在标准计算资源上研究它们的动力学。我们审查计算技术,以了解在不同环境条件下铁转运蛋白的平衡和动力学性质。在需要进行量子化学处理的细节上,已仔细研究了铁周围的八面体几何形状,并确定了铁配位酪氨酸处于不寻常的去质子化状态。在原子细节上,通过分子动力学(MD)模拟,研究了在不同pH,离子强度和其他金属离子结合条件下转铁蛋白的N瓣和完整双瓣结构。这些研究允许回答以下问题:铁壳中第二个壳残基的功能,协同阴离子在准备结合铁的活性位点中的作用以及N-和C-叶的动力学差异。在FbpA上的MD模拟已导致对磷酸盐与载脂蛋白形式的结合动力学的详细观察,并导致在模仿周质空间提供的环境生态位的条件下,整体形式的构象偏爱。要研究这些蛋白质及其受体的动力学,必须采用粗粒度方法,因为这些系统对于原子模拟来说实在太大了。通过这种方法对人转铁蛋白(hTf)及其致病性受体的复合物的研究揭示了进化战争中出现的防御机制的潜在机理解释。同时,转铁蛋白受体结合的hTf中的运动已显示出不利于apo hTf的解离,这解释了为什么两种蛋白在从内体到细胞表面的循环过程中仍保持复合状态。讨论了与铁转运蛋白中金属离子结合释放相关的开放性问题和可能的技术应用,这些问题可以通过量子力学,MD和粗粒度方法的混合使用来解决。通过这种方法对人转铁蛋白(hTf)及其致病性受体的复合物的研究揭示了进化战争中出现的防御机制的潜在机理解释。同时,转铁蛋白受体结合的hTf中的运动已显示出不利于apo hTf的解离,这解释了为什么两种蛋白在从内体到细胞表面的循环过程中仍保持复合状态。讨论了与铁转运蛋白中金属离子结合释放相关的开放性问题和可能的技术应用,这些问题可以通过量子力学,MD和粗粒度方法的混合使用来解决。通过这种方法对人转铁蛋白(hTf)及其致病性受体的复合物的研究揭示了进化战争中出现的防御机制的潜在机理解释。同时,转铁蛋白受体结合的hTf中的运动已显示出不利于apo hTf的解离,这解释了为什么两种蛋白在从内体到细胞表面的循环过程中仍保持复合状态。讨论了与铁转运蛋白中金属离子结合释放相关的开放性问题和可能的技术应用,这些问题可以通过量子力学,MD和粗粒度方法的混合使用来解决。已经显示,与运铁蛋白受体结合的hTf中的运动不利于apo hTf的解离,这解释了为什么两种蛋白在从内体到细胞表面的循环过程中仍保持复合状态。讨论了与铁转运蛋白中金属离子结合释放相关的开放性问题和可能的技术应用,这些问题可以通过量子力学,MD和粗粒度方法的混合使用来解决。已经显示,与运铁蛋白受体结合的hTf中的运动不利于apo hTf的解离,这解释了为什么两种蛋白在从内体到细胞表面的循环过程中仍保持复合状态。讨论了与铁转运蛋白中金属离子结合释放相关的开放性问题和可能的技术应用,这些问题可以通过量子力学,MD和粗粒度方法的混合使用来解决。
更新日期:2017-09-20
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