Characterizing and Predicting Protein Hinges for Mechanistic Insight
Characterizing and Predicting Protein Hinges for Mechanistic Insight
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DOI：
10.1016/j.jmb.2019.11.018
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发表时间：
2020-01-17
影响因子：
5.6
通讯作者：
Jernigan, Robert L.
中科院分区：
文献类型：
--
作者：
Khade, Pranav M.;Kumar, Ambuj;Jernigan, Robert L.
蛋白质的功能需要高度特定的动力学，这在很大程度上取决于氨基酸如何包装的细节。铰链运动是最常见的大运动类型，以酶在其底物周围的打开和关闭为典型。这里用图论来描述残数的堆积和几何形状。这种特性足以从单个静态结构中实现可靠的铰链预测，值得注意的是，这可以来自结构的开放或封闭形式。这种在蛋白质结构中识别铰链的新方法被称为PACKMAN。通过对b因子的排列试验对预测铰链进行了验证。将铰链预测结果与人工整理的铰链残基列表进行比较，结果表明PACKMAN具有足够的鲁棒性，可以重现已知的构象变化，并且能够从蛋白质的开放或封闭形式同样好地预测铰链区域。已经研究了167组具有开放和封闭结构的蛋白质对，并给出了一些其他蛋白质的例子，包括寨卡病毒非结构化（NS）蛋白，其中NS5蛋白中有6个铰链区域，NS3蛋白酶复合物结合的NS2B中有5个铰链区域，NS3解旋酶蛋白中有5个铰链。从该方法获得的结果对于生成用于药物设计的蛋白质靶点的构象集成具有重要意义。PACKMAN可以免费访问（https://PACKMAN.bb.iastate）。edu/)。(C) 2019年Elsevier Ltd.出版
The functioning of proteins requires highly specific dynamics, which depend critically on the details of how amino acids are packed. Hinge motions are the most common type of large motion, typified by the opening and closing of enzymes around their substrates. The packing and geometries of residues are characterized here by graph theory. This characterization is sufficient to enable reliable hinge predictions from a single static structure, and notably, this can be from either the open or the closed form of a structure. This new method to identify hinges within protein structures is called PACKMAN. The predicted hinges are validated by using permutation tests on B-factors. Hinge prediction results are compared against lists of manually curated hinge residues, and the results suggest that PACKMAN is robust enough to reproduce the known conformational changes and is able to predict hinge regions equally well from either the open or the closed forms of a protein. A group of 167 protein pairs with open and closed structures has been investigated Examples are shown for several additional proteins, including Zika virus nonstructured (NS) proteins where there are 6 hinge regions in the NS5 protein, 5 hinge regions in the NS2B bound in the NS3 protease complex and 5 hinges in the NS3-helicase protein. Results obtained from this method can be important for generating conformational ensembles of protein targets for drug design. PACKMAN is freely accessible at (https://PACKMAN.bb.iastate. edu/). (C) 2019 Published by Elsevier Ltd.