人工核酸切割分子与核酸相互作用的研究
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摘要
人工核酸切割分子,又称人工核酸酶,是用化学方法合成的一类能模拟天然核酸酶断裂核酸骨架的功能小分子。它可以发展成为有用的分子生物学工具和基因治疗药物。本论文设计合成了一系列人工核酸断裂分子,通过多种实验手段研究了它们与核酸间的结合,断裂及凝聚作用。
本文选用对核酸碱基具有特异性识别能力的聚酰胺体系作为修饰分子,选用具有典型水解及自由基氧化断裂机理的双苯并咪唑(IDB),单双大环多胺(Cyclen or bis-Cyclen)和抗坏血酸(Vc)为模型化合物,通过不同结构柔性手臂连接构成一系列新型核酸切割分子。旨在利用聚酰胺对核酸的特异性识别能力,提高和增强切割分子对核酸断裂的选择性及位点专一性。利用化学合成的方法对上述新型切割分子进行合成及结构表征。
在切割分子对核酸的相互作用研究中,首先利用琼脂糖凝胶电泳方法对比研究了三类切割小分子(IDB, Bis-Cyclen and Vc)与通过聚酰胺修饰后的新型断裂试剂(Polyamide-IDB, Polyamide-Bis-Cyclen and Polyamide-Vc)对核酸断裂作用的差异。实验结果显示,聚酰胺修饰后的切割分子,在相同条件下与原始切割分子相比对核酸的断裂能力明显增加,在较低的切割浓度下,可通过双链切割有效将核酸断裂为线形DNA。这种经聚酰胺修饰提高核酸断裂能力的结果不仅适用于水解型断裂分子IDB和Cyclen,也适用于自由基氧化型断裂分子Vc。此外,利用模型分析可知,Vc对核酸具有较明显的随机性双链断裂能力,通过聚酰胺对Vc分子的修饰,将其对核酸的作用过程转变为有选择性的非随机性双链断裂。
在人工核酸断裂分子与核酸结合能力研究中,我们先后通过圆二色光谱,核酸熔点,荧光淬灭,紫外吸收光谱及Maldi-Tof等一系列光谱及质谱方法量化分析了小分子断裂试剂在通过聚酰胺体系修饰前后对核酸亲和能力的变化。通过对比淬灭常数C50,核酸熔点差△Tm及表观结合常数Kapp等结合常数可知,聚酰胺分子的引入,使小分子切割试剂与核酸间的相互作用增强,亲和力增加,作用模式由较弱的静电吸引作用转化为较强的沟槽式结合,并显示出聚吡咯单元的聚酰胺分子对核酸中富AT序列具有明显的特异性结合作用。
在研究中我们意外发现,含酰胺结构的多胺类分子金属配合物在一定条件下对核酸具有凝聚作用。为此,我们以双苯并咪唑(IDB),三氮九员环多胺(TACN),四氮十二员环多胺(Cyclen)为模型化合物,分别连接正丁基,正丁酰基和乙酸乙酯构成九种不同结构不同侧链的多胺类小分子配体,讨论酰胺中羰基的存在及位置对核酸凝聚的影响。首先合成并表征了上述九种配体分子及其金属配合物。
利用琼脂糖凝胶电泳对比了多胺分子中不含羰基,含邻位羰基及间位羰基与核酸的相互作用,结果显示,只有侧链中含邻位羰基的多胺分子(即具有酰亚胺结构)在一定条件下对核酸具有凝聚作用,具有间位羰基的分子作用较弱,而含烷基侧链的多胺分子对核酸无凝聚作用。其中,金属锌配合物在一定条件下可使pUC18质粒DNA凝聚成为1000bp左右的条带,而金属铜配合物在凝聚核酸同时,对核酸进行不同程度的切割,因而凝聚成大小不同的核酸颗粒,电泳中显示为弥散条带。此外,通过浓度、温度及时间梯度对比实验证实,含邻位羰基的多胺类金属配合物对核酸的凝聚作用只发生在50℃和较高配合物浓度下,即配合物浓度与反应温度是发生凝聚作用的必要条件。选用不同种类的核酸进行实验发现,这种在一定条件下发生的凝聚作用对不同种类的核酸具有一定普遍性。
原子力显微镜结果显示,这种凝聚作用是以带正电的小分子配合物为中心,通过静电或氢键作用,使核酸分子向内收缩,形成形态及大小相近的颗粒。
Artificial nuclease can mimic the function of natural nuclease by breaking the backbone of DNA site-specifically. And these small molecules can also be used as molecular biology tools and gene therapy agents. The present dissertation reported the design and synthesis of a series of artificial nuclease, and their detailed DNA binding, DNA cleavage and DNA condensation behaviors were also studied by many different experimental methods.
In this paper, polyamides which have sequence-specificity to bases were chose as modificators and bis(2-benzimidazolylmethyl)amine (IDB), polyamines (Cyclen) with hydrolysis mechanism and ascorbic acid (Vc) with oxidative mechanism were chose as model compounds. Two parts above were linked by different flexible linker to form a series of new artificial nucleases. We expected that cleavage ability and sequence-specificity of small molecules were enhanced through the modification of polyamides. The cleavage agents mentioned above were synthesized and characterized.
In the process of interaction research between cleavage agents and nucleic acid, gel electrophoresis experiences were performed to analysis the DNA cleavage discrepancy of three kinds of cleavage agents in the absence or presence of polyamide. The results showed that DNA cleavage ability of molecules modified by polyamide was stronger than that of original cleavage agents apparently in the same condition, and they can cleave duplex to form linear DNA through double strand cleavage in the lower concentration. Both hydrolytic (IDB& Cyclen) and oxidative (Vc) small cleavage agents are mediated efficiently by modification of polyamide moiety. In addition, statistic data suggested that the process of DNA cleavage resulted from Vc is completely random, but that of Vc modified by polyamide is selectivity and non-random.
In the research of binding ability of cleavage agents and DNA, circular dichroism, DNA melting point, fluorescence quenching, UV spectrum and Maldi-Tof mass spectrometry were performed to quantify the affinity of cleavage agents in the absence and presence of polyamide to DNA. The data of binding constant, including C50,ΔTm and Kapp, showed that the interaction and affinity between cleavage agents and DNA increased apparently due to the introduction of polyamide. The binding mode has changed from electrostatic interaction to minor groove binding. The outstanding results further supported A-T rich sequences preference of cleavage agents in the presence of polyamide containing pyrrole units.
An accident discovery happened in the research. Polyamine complexes containing imide can condense DNA to small particles under some condition. So, IDB, TACN and Cyclen were chose as model compounds and different side chains were linked, and nine polyamine ligands with different structures side chains were synthesized and characterized to discuss the effect of carbonyl to DNA condensation.
The gel electrophoresis showed that polyamine with ortho-position carbonyl can condense DNA efficiently. However, the weak and none effect were obtained by the same ligand with meta-position carbonyl and without carbonyl, respectively. Zinc complex can condense pUC18 plasmid DNA to small particles which size is like about 1000bp band, but copper complex can cleave DNA while condense DNA to small particles with different sizes, showing smear band in the gel. Through the further experiments of concentration, temperature and time-dependence assay, we found that one of the necessary conditions is high temperature (50℃), and the other is higher concentration of reaction. The same assay was performed by choosing different kinds of DNA, and results demonstrated that the DNA condensation under some condition is general application.
Atom force microscopy assay indicated that DNA condensation was centered on small molecules with positive charge, and DNA was condensed into the same or similar size particles with electrostatic interaction or hydrogen band.
本文选用对核酸碱基具有特异性识别能力的聚酰胺体系作为修饰分子,选用具有典型水解及自由基氧化断裂机理的双苯并咪唑(IDB),单双大环多胺(Cyclen or bis-Cyclen)和抗坏血酸(Vc)为模型化合物,通过不同结构柔性手臂连接构成一系列新型核酸切割分子。旨在利用聚酰胺对核酸的特异性识别能力,提高和增强切割分子对核酸断裂的选择性及位点专一性。利用化学合成的方法对上述新型切割分子进行合成及结构表征。
在切割分子对核酸的相互作用研究中,首先利用琼脂糖凝胶电泳方法对比研究了三类切割小分子(IDB, Bis-Cyclen and Vc)与通过聚酰胺修饰后的新型断裂试剂(Polyamide-IDB, Polyamide-Bis-Cyclen and Polyamide-Vc)对核酸断裂作用的差异。实验结果显示,聚酰胺修饰后的切割分子,在相同条件下与原始切割分子相比对核酸的断裂能力明显增加,在较低的切割浓度下,可通过双链切割有效将核酸断裂为线形DNA。这种经聚酰胺修饰提高核酸断裂能力的结果不仅适用于水解型断裂分子IDB和Cyclen,也适用于自由基氧化型断裂分子Vc。此外,利用模型分析可知,Vc对核酸具有较明显的随机性双链断裂能力,通过聚酰胺对Vc分子的修饰,将其对核酸的作用过程转变为有选择性的非随机性双链断裂。
在人工核酸断裂分子与核酸结合能力研究中,我们先后通过圆二色光谱,核酸熔点,荧光淬灭,紫外吸收光谱及Maldi-Tof等一系列光谱及质谱方法量化分析了小分子断裂试剂在通过聚酰胺体系修饰前后对核酸亲和能力的变化。通过对比淬灭常数C50,核酸熔点差△Tm及表观结合常数Kapp等结合常数可知,聚酰胺分子的引入,使小分子切割试剂与核酸间的相互作用增强,亲和力增加,作用模式由较弱的静电吸引作用转化为较强的沟槽式结合,并显示出聚吡咯单元的聚酰胺分子对核酸中富AT序列具有明显的特异性结合作用。
在研究中我们意外发现,含酰胺结构的多胺类分子金属配合物在一定条件下对核酸具有凝聚作用。为此,我们以双苯并咪唑(IDB),三氮九员环多胺(TACN),四氮十二员环多胺(Cyclen)为模型化合物,分别连接正丁基,正丁酰基和乙酸乙酯构成九种不同结构不同侧链的多胺类小分子配体,讨论酰胺中羰基的存在及位置对核酸凝聚的影响。首先合成并表征了上述九种配体分子及其金属配合物。
利用琼脂糖凝胶电泳对比了多胺分子中不含羰基,含邻位羰基及间位羰基与核酸的相互作用,结果显示,只有侧链中含邻位羰基的多胺分子(即具有酰亚胺结构)在一定条件下对核酸具有凝聚作用,具有间位羰基的分子作用较弱,而含烷基侧链的多胺分子对核酸无凝聚作用。其中,金属锌配合物在一定条件下可使pUC18质粒DNA凝聚成为1000bp左右的条带,而金属铜配合物在凝聚核酸同时,对核酸进行不同程度的切割,因而凝聚成大小不同的核酸颗粒,电泳中显示为弥散条带。此外,通过浓度、温度及时间梯度对比实验证实,含邻位羰基的多胺类金属配合物对核酸的凝聚作用只发生在50℃和较高配合物浓度下,即配合物浓度与反应温度是发生凝聚作用的必要条件。选用不同种类的核酸进行实验发现,这种在一定条件下发生的凝聚作用对不同种类的核酸具有一定普遍性。
原子力显微镜结果显示,这种凝聚作用是以带正电的小分子配合物为中心,通过静电或氢键作用,使核酸分子向内收缩,形成形态及大小相近的颗粒。
Artificial nuclease can mimic the function of natural nuclease by breaking the backbone of DNA site-specifically. And these small molecules can also be used as molecular biology tools and gene therapy agents. The present dissertation reported the design and synthesis of a series of artificial nuclease, and their detailed DNA binding, DNA cleavage and DNA condensation behaviors were also studied by many different experimental methods.
In this paper, polyamides which have sequence-specificity to bases were chose as modificators and bis(2-benzimidazolylmethyl)amine (IDB), polyamines (Cyclen) with hydrolysis mechanism and ascorbic acid (Vc) with oxidative mechanism were chose as model compounds. Two parts above were linked by different flexible linker to form a series of new artificial nucleases. We expected that cleavage ability and sequence-specificity of small molecules were enhanced through the modification of polyamides. The cleavage agents mentioned above were synthesized and characterized.
In the process of interaction research between cleavage agents and nucleic acid, gel electrophoresis experiences were performed to analysis the DNA cleavage discrepancy of three kinds of cleavage agents in the absence or presence of polyamide. The results showed that DNA cleavage ability of molecules modified by polyamide was stronger than that of original cleavage agents apparently in the same condition, and they can cleave duplex to form linear DNA through double strand cleavage in the lower concentration. Both hydrolytic (IDB& Cyclen) and oxidative (Vc) small cleavage agents are mediated efficiently by modification of polyamide moiety. In addition, statistic data suggested that the process of DNA cleavage resulted from Vc is completely random, but that of Vc modified by polyamide is selectivity and non-random.
In the research of binding ability of cleavage agents and DNA, circular dichroism, DNA melting point, fluorescence quenching, UV spectrum and Maldi-Tof mass spectrometry were performed to quantify the affinity of cleavage agents in the absence and presence of polyamide to DNA. The data of binding constant, including C50,ΔTm and Kapp, showed that the interaction and affinity between cleavage agents and DNA increased apparently due to the introduction of polyamide. The binding mode has changed from electrostatic interaction to minor groove binding. The outstanding results further supported A-T rich sequences preference of cleavage agents in the presence of polyamide containing pyrrole units.
An accident discovery happened in the research. Polyamine complexes containing imide can condense DNA to small particles under some condition. So, IDB, TACN and Cyclen were chose as model compounds and different side chains were linked, and nine polyamine ligands with different structures side chains were synthesized and characterized to discuss the effect of carbonyl to DNA condensation.
The gel electrophoresis showed that polyamine with ortho-position carbonyl can condense DNA efficiently. However, the weak and none effect were obtained by the same ligand with meta-position carbonyl and without carbonyl, respectively. Zinc complex can condense pUC18 plasmid DNA to small particles which size is like about 1000bp band, but copper complex can cleave DNA while condense DNA to small particles with different sizes, showing smear band in the gel. Through the further experiments of concentration, temperature and time-dependence assay, we found that one of the necessary conditions is high temperature (50℃), and the other is higher concentration of reaction. The same assay was performed by choosing different kinds of DNA, and results demonstrated that the DNA condensation under some condition is general application.
Atom force microscopy assay indicated that DNA condensation was centered on small molecules with positive charge, and DNA was condensed into the same or similar size particles with electrostatic interaction or hydrogen band.
引文
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