Investigating Polyoxometalate-Protein Interactions at Chemically Distinct Binding Sites
Investigating Polyoxometalate-Protein Interactions at Chemically Distinct Binding Sites
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DOI：
10.1021/acs.jpcb.8b02931
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发表时间：
2018-07-26
影响因子：
3.3
通讯作者：
Prabhakar, Rajeev
中科院分区：
文献类型：
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作者：
Paul, Thomas J.;Parac-Vogt, Tatjana N.;Prabhakar, Rajeev
在这项研究中，结合分子对接（刚性和柔性）和全原子分子动力学模拟技术，研究了1:1含zr的Keggin多金属氧酸盐（ZrK）与人血清白蛋白（HSA）四个化学上不同的切割位点[Arg114-Leu115（位点1），Ala257-Asp258（位点2），Lys313-Asp314（位点3）和Cys392-Glu393（位点4）]的相互作用。采用静电电位、氨基酸残基化学性质、结合自由能和二级结构等参数对ZrK-HSA络合物进行了分析。他们认为ZrK以一种相当独特的方式结合到不同的裂解位点，其结合主要是氢键，直接和溶剂介导，以及静电相互作用，正如实验所表明的那样。计算的结合自由相互作用能（位点1、位点2、位点3和位点4分别为-575、-24.2、-50.8和-91.2 kJ/mol）预测了一个主要结合位点（位点4）和三个次要结合位点（位点1、位点2和位点3）的存在。等温量热实验也证实了这种结合的强放热性。此外，ZrK的结合并没有改变HSA的整体α -螺旋二级结构，这与实验观察一致。此外，发现底物的肽键水解可以保持其整体结构。这些结果为ZrK复合物与蛋白质的相互作用提供了更深入的了解，它们将导致设计下一代具有更高水解活性的催化活性多金属氧酸盐。
In this study, a combined molecular docking (rigid and flexible) and all-atom molecular dynamics simulations technique have been employed to investigate interactions of 1:1 Zr-containing Keggin polyoxometalate (ZrK) with four chemically distinct cleavage sites [Arg114-Leu115 (site 1), Ala257-Asp258 (site 2), Lys313-Asp314 (site 3), and Cys392-Glu393 (site 4)] of human serum albumin (HSA). The ZrK-HSA complexations were analyzed using electrostatic potentials, the chemical nature of amino acid residues, binding free energies, and secondary structures as parameters. They suggested that ZrK binds in a rather distinct manner to different cleavage sites, and its association was dominated by hydrogen bonding, both direct and solvent mediated, and electrostatic interactions, as suggested experimentally. The computed binding free interaction energies (-575, -24.2, -50.8, and -91.2 kJ/mol for sites 1, 2, 3, and 4, respectively) predicted the existence of one major binding site (site 4) and three minor binding sites (site 1, site 2, and site 3). The strong exothermicity of the binding was also supported by isothermal calorimetry experiments. Additionally, the binding of ZrK did not alter the overall alpha-helical secondary structure of HSA, which was in line with experimental observation. Furthermore, hydrolysis of the peptide bonds of the substrate was found to retain its overall structure. These results have provided a deeper understanding of the complex ZrK interactions with proteins, and they will lead to the design of the next generation of catalytically active polyoxometalates with improved hydrolytic activities.