Molecular dynamics simulations of complexes between wild-type and mutant anthrax protective antigen variants and a model anthrax toxin receptor.
Molecular dynamics simulations of complexes between wild-type and mutant anthrax protective antigen variants and a model anthrax toxin receptor.
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野生型和突变型炭疽保护性抗原变体与炭疽毒素受体模型之间复合物的分子动力学模拟。
DOI：
10.1080/07391102.2005.10507021
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Nelson,DonaldJ
中科院分区：
文献类型：
--
作者：
Stiles,Linsey;Nelson,DonaldJ
炭疽芽孢杆菌是一种芽胞形成的感染性细菌，其产生的毒素由三种蛋白质组成：致死因子(LF)、水肿因子(EF)和保护性抗原(PA)。LF和EF具有细胞内酶功能，其净作用是严重损害宿主的先天免疫。在炭疽病感染过程中，PA在促进EF和LF毒素进入宿主细胞质方面起着关键作用。已经确定了这三种炭疽毒素的晶体结构，以及(人类)von Willebrand因子A(整合素VWA/I结构域)-炭疽毒素受体的晶体结构。还报道了VWA/I与PA之间的络合物的理论结构。在这里，我们报告了对炭疽保护抗原结构域4(PA-D4)和von Willebrand因子A(VWA/I)之间的复合物进行的1,000个PSEC分子动力学(MD)模拟的结果。使用Insight II软件对含有野生型(WT)PA-D4的复合体以及包含PA-D4的三个不同突变体的复合体进行了MD模拟，其中一个在PA-D4的“小环”(残基679-693)(D683A/L685E/Y688C)中包含三个取代，一个在PA-D4-受体界面的关键位点上包含一个替代(K679A)，另一个在PA的C末端缺失11个残基(A724-735)。所有三组PA突变都已被实验证明会导致PA功能的严重缺陷。我们的MD结果与这些发现是一致的。在MD模拟过程中，观察到突变的PA-D4结构域与炭疽受体之间的相互作用发生了重大中断。当与PA-D4的突变变体形成的VWA复合体受到MD模拟时，PA-D4的许多二级结构特征也受到严重损害。这些MD模拟结果清楚地表明，突变的PA-D4残基在“小环”和羧基末端对于维持能够与炭疽毒素受体有效相互作用的PA构象具有重要意义。
Bacillus anthracis, a spore-forming infectious bacterium, produces a toxin consisting of three proteins: lethal factor (LF), edema factor (EF), and protective antigen (PA). LF and EF possess intracellular enzymatic functions, the net effect of which is to severely compromise host innate immunity. During an anthrax infection PA plays the critical role of facilitating entry of both EF and LF toxins into host cell cytoplasm. Crystal structures of all three of the anthrax toxins have been determined, as well as the crystal structure of the (human) von Willebrand factor A (integrin VWA/I domain)—an anthrax toxin receptor. A theoretical structure of the complex between VWA/I and PA has also been reported. Here we report on the results of 1,000 psec molecular dynamics (MD) simulations carried out on complexes between the Anthrax Protective Antigen Domain 4 (PA-D4) and the von Willebrand Factor A (VWA/I). MD simulations (usingInsight IIsoftware) were carried out for complexes containing wildtype (WT) PA-D4, as well as for complexes containing three different mutants of PA-D4, one containing three substitutions in the PA-D4 “small loop” (residues 679–693) (D683A/L685E/Y688C), one containing a single substitution at a key site at the PA-D4—receptor interface (K679A) and another containing a deletion of eleven residues at the C-terminus of PA (A724–735). All three sets of PA mutations have been shown experimentally to result in serious deficiencies in PA function. Our MD results are consistent with these findings. Major disruptions in interactions were observed between the mutant PA-D4 domains and the anthrax receptor during the MD simulations. Many secondary structural features in PA-D4 are also severely compromised when VWA complexes with mutant variants of PA-D4 are subjected to MD simulations. These MD simulation results clearly indicate the importance of the mutated PA-D4 residues in both the “small loop” and at the carboxyl terminus in maintaining a PA conformation that is capable of effective interaction with the anthrax toxin receptor.