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首页> 外文学位 >Investigation on the relationship between structural flexibility and thermodynamics of DNA: Insights from NMR structural studies of codon 335 of HKNPC-EBV LMP1 gene.
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Investigation on the relationship between structural flexibility and thermodynamics of DNA: Insights from NMR structural studies of codon 335 of HKNPC-EBV LMP1 gene.

机译：结构柔性与DNA热力学之间关系的研究：HKNPC-EBV LMP1基因第335位密码子的NMR结构研究。

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摘要

The DNA local structure is associated with DNA mutation since high DNA repairing efficiency, which is determined by the DNA local structure, prevents mutations from occurring in the genes. This thesis focuses on what these sources are and how they control the DNA local structure which affects its biological functions through recognition. A detailed study of the mechanism of DNA local structure alteration will certainly push forward our understanding on DNA mutation mechanism.;Initially, a DNA hairpin d(CGGTCCATTAGGACCG) containing HKNPC-EBV LMP1 mutant codon 335 (GAC(Asp)) is studied in order to explore the structure and the underlying chemistry of the unique 'Chinese type of LMP1 sequence' in the EBV strain. Without advanced NMR instruments, complicated NMR pulse sequences and isotope labeling of DNA, efforts have been made to develop novel methods, particularly the use of computational methods, to determine DNA structure.;The SingrMM method has been developed and verified to successfully derive the endocyclic sugar torsion angle constraints suitable for the structure determination of solution DNA molecules, and is also shown to be applicable to the study of RNA type molecules. Through incorporation of a E-COSY experiment and the SingrMM method, useful information on both P and gamma can also be determined. It is also demonstrated that alpha, gamma, beta, epsilon and the "noncontact" information could be obtained from 13C chemical shifts, 3JH3'P and 3JCP4' values by performing HSQC experiments and the absence of NOE intensities in NOESY experiments respectively.;Through a detailed analysis of the structure, it has been shown that the relaxation mechanism of the purine-pyrimidine clash assists the process of DNA separation. In addition, the comparison between the structural results for the native (GGC) and the mutant codon (GAC) reveals the presence of a relationship between the sequence and the flexibility.;Analysis of the structural data obtained in this work together with those collected from the PDB demonstrated that the structural flexibility (DeltaSigmaS/DeltaT) and the entropy (DeltaS) is highly correlated and it explains the origin of the structure-stability relationship of DNA tetramer units reported earlier by us. There are at least three mechanisms unveiled, which are depended on the sequence, for the DNA structural changes. Based on a consideration of structural flexibility, a signaling region appears for AT-rich sequences. The redistribution of both solvent molecules and local structures of DNA tetramers are believed to be the origin responsible for the resulting entropy.;Finally, the DFT calculation confirms that the proton transfer in the nucleobase affects the conformation of DNA sugar ring and its backbone conformation, and hence it contributes to the flexibility of DNA which is known to affect its biological function. The protonation of the electronegative atom involved in the hydrogen bonding affects the planarity of DNA basepair and its helical structure. Thus, the process of proton transfer plays a significant role in DNA structural changes.
机译：DNA局部结构与DNA突变相关，因为由DNA局部结构决定的高DNA修复效率可防止基因中发生突变。本文着眼于这些来源是什么，以及它们如何控制通过识别影响其生物学功能的DNA局部结构。对DNA局部结构改变机制的详细研究肯定会推动我们对DNA突变机制的理解。首先，对包含HKNPC-EBV LMP1突变密码子335（GAC（Asp））的DNA发夹d（CGGTCCATTAGGACCG）进行研究。探索EBV株中独特的“中国型LMP1序列”的结构和基础化学。在没有先进的NMR仪器，复杂的NMR脉冲序列和DNA同位素标记的情况下，已努力开发出新的方法，特别是使用计算方法来确定DNA结构。;已经开发并验证了SingrMM方法以成功获得内环糖扭转角约束适合于溶液DNA分子的结构测定，也显示可应用于RNA型分子的研究。通过结合E-COSY实验和SingrMM方法，还可以确定有关P和γ的有用信息。还证明通过分别进行HSQC实验和在NOESY实验中不存在NOE强度，可以从13C化学位移，3JH3'P和3JCP4'值获得α，γ，β，ε和“非接触”信息。详细的结构分析表明，嘌呤-嘧啶对映体的弛豫机制有助于DNA分离过程。此外，对天然（GGC）和突变密码子（GAC）的结构结果的比较揭示了序列和灵活性之间的关系。;分析本工作中获得的结构数据以及从中收集的结构数据PDB证明结构柔韧性（DeltaSigmaS / DeltaT）和熵（DeltaS）高度相关，它解释了我们先前报道的DNA四聚体单元的结构稳定性关系的起源。揭示了至少三种依赖于序列的DNA结构改变的机制。基于结构灵活性的考虑，对于富含AT的序列出现信号区域。溶剂分子和DNA四聚体的局部结构的重新分布被认为是造成熵的原因。最后，DFT计算证实了核碱基中的质子转移会影响DNA糖环的构象及其骨架构象，因此，它有助于DNA的柔韧性，而DNA的柔韧性会影响其生物学功能。氢键所涉及的负电性原子的质子化影响DNA碱基对及其螺旋结构的平面性。因此，质子转移过程在DNA结构变化中起着重要作用。

著录项

  • 作者

    Chiu, Wing Lok Abe Kurtz.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Chemistry Biochemistry.;Biophysics General.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 250 p.
  • 总页数 250
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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