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首页> 外文期刊>The FEBS journal >Molecular dynamics of the DNA-binding domain of the papillomavirus E2 transcriptional regulator uncover differential properties for DNA target accommodation
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Molecular dynamics of the DNA-binding domain of the papillomavirus E2 transcriptional regulator uncover differential properties for DNA target accommodation

机译：乳头瘤病毒E2转录调节子的DNA结合域的分子动力学揭示了DNA靶标调节的不同特性

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摘要

Papillomaviruses are small DNA tumor viruses that infect mammalian hosts, with consequences from benign to cancerous lesions. The Early protein 2 is the master regulator for the virus life cycle, participating in gene transcription, DNA replication, and viral episome migration. All of these functions rely on primary target recognition by its dimeric DNA-binding domain. In this work, we performed molecular dynamics simulations in order to gain insights into the structural dynamics of the DNA-binding domains of two prototypic strains, human papillomavirus strain 16 and the bovine papillomavirus strain 1. The simulations underline different dynamic features in the two proteins. The human papillomavirus strain 16 domain displays a higher flexibility of the beta 2-beta 3 connecting loop in comparison with the bovine papillomavirus strain 1 domain, with a consequent effect on the DNA-binding helices, and thus on the modulation of DNA recognition. A compact beta-barrel is found in human papillomavirus strain 16, whereas the bovine papillomavirus strain 1 protein is characterized by a loose beta-barrel with a large number of cavities filled by water, which provides great flexibility. The rigidity of the human papillomavirus strain 16 beta-barrel prevents protein deformation, and, as a consequence, deformable spacers are the preferred targets in complex formation. In contrast, in bovine papillomavirus strain 1, a more deformable beta-barrel confers greater adaptability to the protein, allowing the binding of less flexible DNA regions. The flexibility data are confirmed by the experimental NMR S-2 values, which are reproduced well by calculation. This feature may provide the protein with an ability to discriminate between spacer sequences. Clearly, the deformability required for the formation of the Early protein 2 C-terminal DNA-binding domain-DNA complexes of various types is based not only on the rigidity of the base sequences in the DNA spacers, but also on the intrinsic deformability properties of each domain.
机译：乳头瘤病毒是感染哺乳动物宿主的小DNA肿瘤病毒，其后果是良性到癌性病变。早期蛋白2是病毒生命周期的主要调控因子，参与基因转录，DNA复制和病毒附加体迁移。所有这些功能都依赖于其二聚体DNA结合结构域对主要靶标的识别。在这项工作中，我们进行了分子动力学模拟，以深入了解两种原型菌株（人乳头瘤病毒株16和牛乳头瘤病毒株1）的DNA结合结构域的结构动力学。模拟强调了这两种蛋白的不同动力学特征。 。与牛乳头瘤病毒株1域相比，人乳头瘤病毒株16域显示出更高的beta 2-beta 3连接环灵活性，从而对DNA结合螺旋产生影响，从而对DNA识别的调节产生影响。在人乳头瘤病毒株16中发现了一个紧凑的β桶，而牛乳头瘤病毒1株蛋白的特征是一个松散的β桶，其中充满了大量的水，这提供了很大的灵活性。人乳头瘤病毒株16β-桶的刚度可防止蛋白质变形，因此，可变形的间隔基是复合物形成中的首选靶标。相反，在牛乳头瘤病毒株1中，更易变形的β-桶赋予该蛋白质更大的适应性，从而允许结合较不灵活的DNA区域。通过实验NMR S-2值确认了柔韧性数据，该值可以通过计算很好地再现。该特征可以为蛋白质提供区分间隔序列的能力。显然，形成各种类型的早期蛋白质2 C端DNA结合域-DNA复合物所需的可变形性不仅取决于DNA间隔区中碱基序列的刚度，而且还取决于其内在的可变形性。每个域。

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