【作者】 陈动；

【导师】 周立新；

【作者基本信息】 暨南大学 ， 无机化学， 2006， 硕士

【摘要】 DNA双螺旋链是储存和传递遗传信息的重要载体。在DNA中碱基配对的高度专一性保证DNA复制的高度精确性，所以在DNA的复制过程中必须保持碱基配对的完整性。但是在DNA复制过程中生物体内在和外在因素会影响碱基之间正常配对，造成碱基错配，致使DNA复制发生错误。 生物体内G∶C、A∶T Watson-Crick配对与非Watson-Crick配对共同存在，不考虑外在因素影响，生物体内仍有以下几种可能的错配：G∶T，G∶U，G∶G，A∶A，G∶A，C∶C，T∶T，U∶U，C∶T，C∶U，这些错配在DNA的复制中经常出现。虽然少数错配会有一些生物功能比如G∶U错配能使Group Ⅰ introns催化中心的四级结构易于形成，并通过Mg²⁺稳定核糖酶的过渡态，但是大多数的错配对DNA的复制有阻碍作用。这些错配基本上都能被系统修复酶所修复。 很多外在因素比如烷基化物能对生物体的DNA碱基配对造成一定损伤，烷基化剂通过与核酸碱基作用从而破坏碱基之间的正常配对或碱基与蛋白质之间的作用，造成碱基错配。如果这些损伤不及时被修复，将会引起一系列的生理疾病，甚至可能引起癌症等。实验研究表明一些人工修复酶能对这些损伤进行修复。所以，探讨烷基化损伤机理将有助于人工修复酶的开发，也能给药物的开发带来一定的参考意义。 本文采用量子化学从头算方法重点研究了核酸碱基的甲基化情况。从甲基化对嘌呤碱基电荷的影响，到甲基化引起碱基配对的改变造成碱基配对的诱变等都作了较为详细的探讨；在对甲基化诱变的探讨中，我们进行了热力学和动力学方面的研究，同时对碱基之间的质子迁移的难易程度也作了探讨；并在充分考虑水分子存在的情况下研究了甲基化对碱基之间的氢键作用和堆积作用的影响。 研究结果表明，烷基化之所以能造成碱基错配是它可使碱基的质子迁移或烯醇互变现象容易发生，改变原有原子的电荷分布或配对模式，同时碱基自身的互变异构体会跟烷基作用，致使互变异构体能够稳定存在，影响正常碱基配对，引起碱基诱变，造成生理疾病的发生。研究结果还表明甲基化能改变碱基之间的相互作用力，从而改变DNA的稳定构型，造成DNA复制发生错误。更多还原

【Abstract】 The double-helical DNA is a very important intermediate in storing and transferring genetic informations. The high fidelity of DNA replication is guaranteed by the high specificity of nucleic acid（NA） base pairing in DNA. So the integrity of bases pairing must be kept during the DNA replication. But inherent and extrinsic factors of organism would influence the normal base pairs in the course of DNA replication, causing the base mispairing and DNA replication errors.G:C and A:T Watson-Crick base pairs and non-Watson-Crick base pairs are coexist in organism. Not considering others influence, there are still several possible mispairing such as G:T and G:U, and so on, which often occur in DNA replication. Although a minority of mispairing may has some biological functions, for instance, G:U mispairing can make the structures of Group I introns easily to form and stabilize the transition state through Mg²⁺, the majority of mispairing would block DNA replication.Many extrinsic factors such as alkylating can bring lesions to DNA base pairs, the alkylating destroy the normal base pairing or interaction between bases and proteins by connecting to NA bases. These lesions would lead to some sicks or even cancer if they would not be repaired in time. Experimental studies suggest that some manual repaired enzymes will repair those lesions. So, it is very significant to exploring the mechanism of alkylating to help to the development of man-made enzymes and some medicines.In the paper, ab initio quantum chemical was used to studying the methylating of NA bases in detailed. On the discussion about mechanism of mutation of methylating, we explored thermodynamics and dynamic properties on base pairs, investigating the proton transfer on base pairs. And we also research the impact of methylating on hydrogen bond and stacked bond in base pairs under considering water molecules.The rusults show that methylating can make the proton transfering in base pairs easily happened, changing the distribution of charges or the mode of pairing. Tautomers of bases would also interact with methylating, resulting in the stabilization of tautomers. The results also indicate that methylating would change the interaction among base pairs, altering the stabilizaton ofstructures and leading to DNA replication error, consequently.更多还原