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首页> 外文学位 >Applying computational methods in the study of biomolecular systems: The recognition mechanism of DNA repair enzyme Fpg.
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Applying computational methods in the study of biomolecular systems: The recognition mechanism of DNA repair enzyme Fpg.

机译：计算方法在生物分子系统研究中的应用：DNA修复酶Fpg的识别机理。

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摘要

8-oxo-guanine (8OG) is one of the most prevalent forms of oxidative DNA Failure to repair 8OG will lead to cancer and many age-related diseases. For studying pathophysiology of these diseases, it is essential to understand the repair mechanism 8OG in healthy cells. In bacteria, 8OG is excised by formamidopyrimidine glycosylase Fpg) as the initial step in base excision repair. To efficiently excise this lesion, Fpg discriminate between 8OG and an excess of guanine in duplex DNA. We computational methods studying the structural basis underlying this high degree selectivity.;FapydG is another common oxidative DNA lesion involving opening of the imidazole ring. It has similar structure and shares the same precursor with 8OGG and can be excised by the same enzymes as 8OG. We examined the current force field parameters for FapydG and found that the energy barrier of the rotational bond C5-N7 is overestimated. New parameters were calculated and simulations with them can well reproduce the x-ray structures.;DNA sliding and base flipping are two essential motions in DNA lesion searching and recognition. We used targeted MD, umbrella sampling, and long MD simulations (1.6 ms in total) to simulate these two processes. We observed the sliding motions and base pair breaking in our long MD simulations. In the targeted MD simulations, after the forced conformational changes occurred, we observed that the structures of several key residues changed from the original conformations to the new ones, which reproduced the structural differences between x-ray structures at different stages.;In first study free energy calculation methods and point mutation studies have been performed on the comparison of the two binding mode of 8OG. Two different binding modes of 8OG in Fpg/DNA complex have been shown in different structural studies. Our all-atom simulations are consistent with both structures. The syn conformation observed in the crystallographic structure of Fpg obtained from B. stearothermophilus is stabilized through interaction with E77, a non-conserved residue. Replacement of E77 by Ser, creating the Fpg sequence found in E. coli and other bacteria, results in preferred binding of 8OG in the anti conformation.
机译：8-氧代鸟嘌呤（8OG）是氧化DNA的最普遍形式之一。修复8OG失败会导致癌症和许多与年龄有关的疾病。为了研究这些疾病的病理生理学，必须了解健康细胞中8OG的修复机制。在细菌中，通过甲酰胺基嘧啶糖基化酶（Fpg）切除8OG，这是碱基切除修复的第一步。为了有效切除该病变，Fpg在双链DNA中区分8OG和过量鸟嘌呤。我们用计算方法研究了这种高度选择性的基础。FapydG是另一种涉及氧化咪唑环的常见氧化性DNA损伤。它具有相似的结构，并且与8OGG具有相同的前体，并且可以被与8OG相同的酶切除。我们检查了FapydG的当前力场参数，发现旋转键C5-N7的能垒被高估了。计算了新的参数，并用它们模拟可以很好地再现X射线的结构。DNA滑动和碱基翻转是DNA损伤搜索和识别的两个基本动作。我们使用了有针对性的MD，总括采样和较长的MD模拟（总计1.6毫秒）来模拟这两个过程。在长时间的MD模拟中，我们观察到了滑动运动和碱基对断裂。在有针对性的MD模拟中，在强迫构象变化发生后，我们观察到几个关键残基的结构从原始构象变为新构象，从而再现了不同阶段X射线结构之间的结构差异。比较了8OG的两种结合方式，进行了自由能计算方法和点突变研究。在不同的结构研究中已显示出8OG在Fpg / DNA复合物中的两种不同结合方式。我们的全原子模拟与两种结构都一致。从嗜热脂肪芽孢杆菌获得的Fpg晶体结构中观察到的顺式构象通过与非保守残基E77的相互作用而稳定。用Ser取代E77，产生在大肠杆菌和其他细菌中发现的Fpg序列，导致抗构象中8OG的优先结合。

著录项

  • 作者

    Song, Kun.;

  • 作者单位

    State University of New York at Stony Brook.;

  • 授予单位 State University of New York at Stony Brook.;
  • 学科 Biophysics General.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 258 p.
  • 总页数 258
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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