Abstract

The possibility of plutonium (Pu) intake by radiation workers can not be ruled out. Transportation of Pu(IV) to various organs/cells is mainly carried through iron-carrying protein, serum transferrin (sTf), by receptor-mediated endocytosis. Understanding the Pu–sTf interaction is a primary step toward future design of its decorporating agents. We report MD simulations of Pu(IV) binding with sTf and look out for its decorporation at extracellular pH using suitable ligands. MD simulations were carried out in polarizable water environment at different protonation states of the protein. Results unravel the binding motif of Pu(IV): (1) sTf binds the ion in closed conformation at extracellular serum pH with carbonate as synergistic anions, (2) change in protonation state of dilysine (K206 and K296)-trigger and that of the carbonate ion at acidic endosomal pH is found to cause conformational changes of protein, conducive for the heavy ion to be released, although; (3) strong electrostatic interaction between D63 in the binding-cleft and Pu(IV) is found not to ever set free the ion. In an endeavour to decorporate Pu(IV), fragmented molecular form of hydroxypyridinone (HOPO) and catechol (CAM)-based ligands are docked at the binding site (BS) of the protein and metadynamics simulations are conducted. Pu(IV) binding at BS is found to be so strong that it was not detached from BS with the docked HOPO. However, for the identical set of simulation parameters, CAM is found to facilitate dislodging the heavy ion from the protein’s binding influence. Differential behaviour of the two chelators is further explored.

Graphic abstract

Fragmented molecular form of hydroxy-pyridinone (HOPO) and catecholamide (CAM) ligands were docked at the binding-site (BS) of human serum transferrin (sTf) to explore their feasibility as plausible Pu(IV) decorporating agents by employing metadynamics method. CAM was found to dislodge Pu from the sTf BS, while HOPO could not.

中文翻译：

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钚结合的分子动力学模拟及其从人血清转铁蛋白结合裂缝中的装饰。

摘要

不排除辐射工作人员摄入钚（Pu）的可能性。Pu(IV) 向各种器官/细胞的运输主要通过受体介导的内吞作用通过携铁蛋白血清转铁蛋白 (sTf) 进行。了解 Pu-sTf 相互作用是未来设计装饰剂的第一步。我们报告了 Pu(IV) 与 sTf 结合的 MD 模拟，并使用合适的配体寻找其在细胞外 pH 值下的装饰。MD 模拟是在可极化水环境中在蛋白质的不同质子化状态下进行的。结果揭示了 Pu(IV) 的结合基序：(1) sTf 在细胞外血清 pH 值下以封闭构象结合离子，碳酸盐作为协同阴离子，(2)二赖氨酸(K206和K296)-触发器质子化状态的变化和酸性内体pH下碳酸根离子的质子化状态的变化导致蛋白质构象变化，有利于重离子的释放；(3) 发现结合裂缝中的 D63 和 Pu(IV) 之间的强静电相互作用永远不会释放离子。在努力装饰 Pu(IV) 的过程中，羟基吡啶酮 (HOPO) 和儿茶酚 (CAM) 基配体的碎片化分子形式停靠在蛋白质的结合位点 (BS) 上，并进行了元动力学模拟。发现 BS 处的 Pu(IV) 结合非常强，以至于它不会与对接的 HOPO 与 BS 分离。然而，对于相同的一组模拟参数，发现 CAM 有助于从蛋白质的结合影响中去除重离子。

图形摘要

羟基吡啶酮 (HOPO) 和儿茶酚酰胺 (CAM) 配体的碎片分子形式停靠在人血清转铁蛋白 (sTf) 的结合位点 (BS)，以通过使用元动力学方法探索它们作为合理的 Pu(IV) 装饰剂的可行性。发现 CAM 可以将 Pu 从 sTf BS 中移出，而 HOPO 则不能。