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Modeling the Interactions of the Nucleotide Excision Repair UvrA2 Dimer with DNA

机译：用DNA模拟核苷酸切除修复UvrA2二聚体的相互作用

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The UvrA protein initiates the DNA damage recognition process by the bacterial nucleotidenexcision repair (NER) system. Recently, crystallographic structures of holo-UvrA2 dimers from two differentnmicroorganisms have been released (Protein Data Bank entries 2r6f, 2vf7, and 2vf8). However, the details ofnthe DNA binding by UvrA2 and other peculiarities involved in the damage recognition process remain unknown.nWe have undertaken a molecular modeling approach to appraise the possible modes of DNA-UvrA2 inter-naction using molecular docking and short-scale guided molecular dynamics [continuum field, constrained,nand/or unrestricted simulated annealing (SA)], taking into account the three-dimensional location of a seriesnof mutation-identified UvrA residues implicated in DNA binding. The molecular docking was based on thenassumptions that the UvrA2 dimer is preformed prior to DNA binding and that no major protein conformationalnrearrangements, except moderate domain reorientations, are required for binding of undamaged DNA. As anfirst approximation, DNA was treated as a rigid ligand. From the electrostatic relief of the ventral surface ofnUvrA2, we initially identified three, noncollinear DNA binding paths. Each of the three resulting nucleoproteinncomplexes (C1, C2, and C3) was analyzed separately, including calculation of binding energies, the numbernand type of interaction residues (including mutated ones), and the predominant mode of translational andnrotational motion of specific protein domains after SA to ensure improved DNA binding. The UvrA2 dimerncan accommodateDNA in all three orientations, albeit with different binding strengths. One of theUvrA2-DNAncomplexes (C1) fulfilled most of the requirements (high interaction energy, proximity of DNA to mutatednresidues, etc.) expected for a natural, high-affinity DNA binding site. This nucleoprotein presents a structuralnorganization that is designed to clamp and bend double-strandedDNA.We examined the binding site inmorendetail by docking DNAs of significantly different (AT- vs CG-enriched) sequences and by submitting thencomplexes to DNA-unrestricted SA. It was found that in a manner independent of the DNA sequence andnappliedMDprotocols,UvrA2 favors binding of a bent and unwound undamagedDNA, with a kink positioned innthe proximity of the Zn3 hairpins, anticollinearly aligned at the bottom of the ventral protein surface. It isnfurther hypothesized that the Zn3 modules play an essential role in the damage recognition process and thatnthe apparent existence of a family ofDNA binding sitesmight be biologically relevant. Our data should provento be useful in rational (structure-based) mutation studies.
机译：UvrA蛋白通过细菌核苷酸切除修复（NER）系统启动DNA损伤识别过程。最近，已经发布了来自两种不同微生物的全UvrA2二聚体的晶体结构（蛋白质数据库条目2r6f，2vf7和2vf8）。然而，关于UvrA2与DNA结合的细节以及损伤识别过程中涉及的其他特性的细节仍然未知。我们已经采取了一种分子建模方法，利用分子对接和短程引导的分子动力学来评估DNA-UvrA2相互作用的可能模式。 [连续场，受约束的，无限制的和/或不受限制的模拟退火（SA）]，考虑到涉及DNA结合的一系列突变识别的UvrA残基的三维位置。分子对接是基于这样的假设，即UvrA2二聚体是在结合DNA之前形成的，并且除中等结构域重新取向外，不需要任何主要的蛋白质构象重排来结合未受损的DNA。作为第一近似，将DNA视为刚性配体。从nUvrA2腹侧表面的静电释放，我们最初确定了三种非共线DNA结合途径。分别分析了三个产生的核蛋白复合物（C1，C2和C3）中的每一个，包括计算结合能，相互作用残基的数量和类型（包括突变的残基）以及SA后特定蛋白结构域的翻译和旋转运动的主要方式。以确保改善DNA结合。尽管结合强度不同，但UvrA2二聚体可以在所有三个方向上容纳DNA。一种UvrA2-DNA复合物（C1）满足了天然，高亲和力DNA结合位点的大部分要求（高相互作用能，DNA与突变残基的接近度等）。这种核蛋白呈现了一个结构化组织，旨在钳制和弯曲双链DNA。我们通过对接显着不同（富含AT-CG的）序列的DNA并随后将复合物呈递给DNA不受限制的SA，检查了结合位点inmorendetail。已发现，UvrA2以与DNA序列和未应用的MD协议无关的方式，有利于弯曲和未缠绕的未损伤DNA的结合，并且扭结位于Zn3发夹的附近，并在腹侧蛋白质表面的底部反共线排列。进一步假设Zn3模块在损伤识别过程中起重要作用，并且DNA结合位点家族的明显存在可能与生物学有关。我们的数据应被证明对合理的（基于结构的）突变研究有用。

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  • 来源
    《Biochemistry》 |2010年第51期|p.10912-10924|共13页
  • 作者

    Tsvetan G. Gantchev and Darel J. Hunting;

  • 作者单位

    Center for Research in Radio-Oncology (CR2), Department of Nuclear Medicine and Radiobiology,Faculty of Medicine and Life Sciences, Universitu0001 e de Sherbrooke, Sherbrooke, Quu0001 ebec, J1H 5N4 Canada;

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