基于新型分子信标和胸腺嘧啶—汞（Ⅱ）配位作用的DNA和Hg~（2+）检测技术研究
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摘要
随着人类基因组计划的完成,科学工作者的研究重心开始由单纯的获取和收集基因组信息向通过基因信息分析对生命过程做出预报和新发现转移。因此,在后基因组和蛋白质组时代,迫切需要发展高灵敏、高选择性的定量研究基因组信息的工具。分子信标就是最理想的工具之一。因其独特的性质和多功能性,分子信标已被广泛应用于核酸的实时定量检测、活体分析、化学与生物传感器、疾病诊断等领域。为满足不同的需要,在经典分子信标的基础上,人们设计了许多新型的分子信标。分子信标的迅速发展,为基因组和蛋白质组研究、疾病的分子诊断以及新药开发提供了一个平台。
鉴于汞离子对环境和人类健康的危害,发展简单、快速、低成本的汞离子检测技术对生命、环境、医学以及工农业生产等都具有重要的意义。核酸的结构和功能对重金属离子非常敏感,因此,构建基于核酸的汞离子生物传感器引起人们的关注。近年来,有人报道核酸中thymine能与汞离子特异性结合,形成T-Hg2+-T配合物。之后,T-Hg2+-T配合化学成为构建汞离子生物传感器研究的热点。本文主要致力于DNA检测的新型分子信标的设计和基于T-Hg2+-T配位作用的新型汞离子检测技术的构建。具体内容如下：
第一章绪论
首先系统介绍了分子信标的发现及应用研究,包括分子信标结构、工作原理、优化设计及应用现状。接着介绍了基于T-Hg2+-T配位作用的汞离子生物传感器的研究进展。最后阐述了本论文设计思路和研究意义,指出论文的创新之处。
第二章基于电活性-非电活性转换分子信标直接均相检测DNA
本章设计了一种新型的电化学分子信标,即“电活性-非电活性转换分子信标”,直接用于均相检测DNA。该电化学分子信标由一段3’、5’端标记有电化学标记物胭脂红酸,自身能够形成茎-环结构的单链寡核苷酸组成(简称为CAs-MB)。CAs-MB在关闭状态时,两端标记的胭脂红酸单体在茎部互补序列的作用下相互接近,并形成二聚体,从而导致电化学信号的淬灭；与完全互补目标DNA序列杂交时,CAs-MB将发生构象转换,即由自由卷曲的茎-环结构转换为刚性的DNA双链,胭脂红酸二聚体变为单体,从而恢复了胭脂红酸单体的电信号。CAs-MB的电化学信号强度与完全互补目标DNA序列的浓度在0.06-1.4μM范围内成良好线性关系,相关系数为0.998,检出限为30nM。该电化学分子信标能够像传统的荧光分子信标一样有效地识别单碱基错配。CAs-MB有望直接应用于精确地基因分析。
第三章基于非标记分子信标修饰的金胶纳米探针的非交联性聚集比色检测单核苷酸多态性
基于非标记分子信标(Label-free molecular beacon, LMB)修饰的金胶纳米颗粒(AuNPs)的非交联聚集,本章构建了一种新型比色检测单核苷酸多态性的方法。该方法将茎-环结构的分子信标高特异性识别力和金胶纳米颗粒聚集变色的光学特性有机结合在一起,实现了单核苷酸多态性的比色检测。利用金胶纳米的自组装技术将巯基修饰的分子信标探针固定到金胶表面制备分子信标修饰的金胶纳米探针(AuNPs-LMB)。当AuNPs-LMB与不同的目标序列(野生型或突变型)杂交时,金胶表面的LMB的构象由茎-环结构转换为具有一定刚性的双链并引起金胶体系熵、焓的差异性；在适当盐度条件下,AuNPs-LMB对不同目标序列的识别导致金胶纳米颗粒不同程度的聚集,从而实现对SNPs的识别。将该比色传感体系应用于P53基因的单核苷酸多态性的检测,结果令人满意。
第四章基于多胸腺嘧啶寡核苷酸修饰的金电极高灵敏伏安检测汞离子
利用胸腺嘧啶(thymine, T)与汞离子的高亲和识别作用和电化学溶出技术,本章设计了一种具有高灵敏度和高选择性的汞离子生物传感器-多胸腺嘧啶寡核苷酸修饰的金电极即Polythymine oligonucleotide/Au电极(PTO/Au电极)。将一段巯基修饰的polythymine oligonucleotide (5'-SH-T15-3')通过Au-S键自组装到金电极表面上,然后用巯基己醇封闭电极表面即得到PTO/Au电极。利用PTO/Au电极上DNA序列中的碱基T与Hg2+特异性结合的作用选择性把Hg2+富集于电极表面,缓冲液洗涤几次后,在lOmM HEPES (pH7.2, 1M NaClO4)溶液中将富集的Hg2+电化学还原成Hg,然后进行阳极溶出伏安扫描测定汞的氧化电流信号。此修饰电极对Hg2+的响应在0.2-1 nmol/L范围内成良好的线性关系,相关系数为0.9953,检测限达60 pM。另外,此修饰电极在Zn2+、Pb2+等其他六种二价金属离子的存在下并不干扰对Hg2+的检测(nM2+:nHg2+=200:1)。与传统的电化学溶出检测汞离子的方法相比,PTO/Au电极展现了良好的灵敏度和选择性,是一种新型高效的检测汞离子的“绿色”化学修饰电极。
第五章基于汞特异性DNA修饰的金胶纳米探针的比色传感器简便快速检测汞离子
本章制备了一种汞特异性DNA (mercury-specific DNA, MSD)修饰的金胶纳米(Au-MSD)比色探针。该探针通过汞离子操纵修饰在金胶表面的汞特异性DNA的构象转换来调节金胶抵抗盐诱导聚集的能力,从而实现汞离子的简便快速的比色检测。溶液中不存在汞离子时,修饰在金胶表面的汞特异性DNA以随意卷曲的单链构象存在,当再加入一定浓度的MgCl2时,该探针会因为金胶颗粒彼此间的静电排斥力的急剧降低而迅速聚集；相反,溶液中存在汞离子时,汞离子特异性DNA识别汞离子并发生一个由自由卷曲的单链构象向汞介导的“发卡型”刚性双链的转换过程,这些在金胶表面形成的刚性双链大大提高了金胶抵抗盐诱导聚集的能力,致使同样的盐浓度下金胶也不会发生聚集；伴随着上述变化过程,金胶溶液的颜色也由紫红色转变成酒红色,而溶液颜色的变化程度与汞离子的浓度相关。此纳米比色探针对0μM-10μM浓度范围内的汞离子产生良好的响应,检测限为60nM(S/N=3),并应用于实际水样中汞离子的检测。
第六章基于三聚硫氰酸修饰的金胶纳米探针的比色传感系统简便快速检测汞离子
本章利用汞离子的亲巯基性和金胶纳米颗粒的独特光学性质,建立了一种基于三聚硫氰酸(TCA)修饰的金胶纳米探针(TCA-AuNPs)的简单、快速检测汞离子的比色传感方法。表面覆盖有柠檬酸三钠的金胶纳米颗粒与三聚硫氰酸通过配体交换反应制备TCA-AuNPs。TCA分子中的巯基使金胶纳米颗粒表面带有较高密度的负电荷,因而TCA-AuNPs之间相互排斥,所以TCA-AuNPs能够稳定分散在溶液中,溶液颜色呈现酒红色。一旦在TCA-AuNPs溶液中加入一定量的Hg2+, TCA-AuNPs表面的巯基就会与Hg2+配位,导致金胶纳米颗粒的快速聚集,溶液的颜色也由酒红色瞬间变为蓝灰色。金胶纳米颗粒的聚集程度与加入的Hg2+的浓度相关。本章详细探讨了TCA组装密度、不同pH的缓冲介质对TCA-AuNPs检测汞离子的灵敏度的影响。在优化的实验条件下,TCA-AuNPs对Hg2+的吸光度比值响应分别在0-1.7μM(y=0.0568x+0.2312,R2=0.9863)和2.0-6.5μM(y=0.2084x-0.2551,R2=0.9739)范围内呈良好的线性关系,最低检测限为50nM(S/N=3)。当加入的金属离子浓度为70μM时,除Pb2+外,Cd2+等其它9种金属离子均不干扰TCA-AuNPs对Hg2+的检测,而Pb2+的干扰可以通过加入掩蔽剂吡啶-2,6-二甲酸(PDCA)加以消除。TCA-AuNPs制备简单,识别汞离子的速度快,而且具有较高的灵敏度高和较好的选择性。因此,该比色传感系统为快速检测Hg2+提供了一种新途径。
With the completion of the human genome project, there has been a rapid shift in focus from simply collecting and archiving genomic data to utilizing genetic analysis for prediction and discovery. The development and utilization of new quantitative tools for research across disciplinary interfaces will prove vital in achieving these objectives. Molecular beacons (MBs) are ideally suited for and hold great promise in genomics and proteomics. More research is expected for MB applications in mutation detection for a variety of disease diagnostics and disease mechanism studies. Gene expression monitoring in living cells and tissues under different conditions with precise quantitation also provides an avenue for further investigation. The extraordinary target-specific capability along with the availability of different fluorophore-quencher pairs makes MB probes extremely useful for multiple analyte applications as well. These properties also make MBs suited for use in the identification of genetic alleles or particular strains of infectious agents. All of these developments will open the possibility of using easily obtainable and designer DNA molecules for genomics and proteomics studies, for molecular diagnosis of diseases, and for new drug development.
Because of continuing concern over mercury in the environment and its deleterious effects on human health, obtaining new mercury detection methods that are cost-effective, rapid, facile and applicable to the environmental and biological milieus is an important goal. This objective has recently emerged as a focal point in the chemistry and, more broadly, sensing communities. DNA's structure and its functioning in the organism are known to be very sensitive to the influence of heavy metals. So, it is very attractive to use DNA-containing systems, e.g., DNA-based biosensors, to perform heavy metal assays. Recently, it has been reported that mercury ions can selectively bind thymine-thymine pairs in DNA sequences to form T-Hg2+-T complexes. For the moment, thymine-Hg2+-thymine chemistry has been highlighted in the development of Hg2+ sensors because thymine-thymine mismatch shows high selectivity to Hg2+ against many other metal ions.
The goal of the present study is to design and research novel molecular beacon and sensors with high sensitivity and selectivity for Hg2+. This paper combines the excellent characteristics of nanoparticles, the specific recognition of molecular recognition elements and the electrochemical technique. The details are given as follows:
Chapter One:Preface
In this chapter, we review the principles, characteristics of molecular beacon and its application in analytical chemistry field. Several assays based on T-Hg2+-T coordination were introduced. Finally, expounded the aim and the significance, pointed out the research content and the innovation in this paper.
Chapter Two:Electrochemically active-inactive switching molecular beacon for direct detection of DNA in homogenous solution
A new kind of electrochemical molecular beacon was reported, termed "electrochemically active-inactive switching molecular beacon", for direct detection of DNA in homogenous solution. The electrochemical molecular beacon consists of a stable stem-loop oligonucleotide carrying two carminic acid moieties (acting as electrochemical reporter) attached at its termini. In a close form, the electrochemical signal is quenched because two carminic acid moieties are close enough to associate into dimer. In the presence of the complementary DNA target, the electrochemical molecular beacon undergoes a conformational transformation from closed (hairpin) to open (linear) structure, which is associated with an increase in electrochemical signal. We found that the electrochemical molecular beacon is as effective as conventional molecular beacon in signaling the presence of complementary target and discriminating targets that differ by a single nucleotide. The proposed electrochemical molecular beacon has a great potential for investigating the interactions of DNA-protein and developing electrochemical real-time polymerase chain reaction.
Chapter Three:colorimetric detection of SNPs based on label-free molecular beacon modified gold nanoparticles through non-crosslinking aggregation
A new colorimetric approach has been developed for the detection of single nucleotide polymorphisms (SNPs). One label-free molecular beacon was immobilized on the surface of gold nanoparticles through Au-S bonds. The sensitive detection of SNPs was achieved by non-crosslinking aggregation of MB-functionalized gold nanoparticles induced by hybridization of target DNA. The mutant target can be determined in a mixed solution containing 19 times higher concentration of wild target. The allele frequency of 5% was accurately determined in a homogeneous and cost-effective manner.
Chapter Four:Polythymine oligonucleotide-modified gold electrode for voltammetric determination of mercury (Ⅱ) in aqueous solution
Polythymine oligonucleotide (PTO)-modified gold electrode (PTO/Au) was developed for selective and sensitive Hg2+ detection in aqueous solutions. This modified electrode was prepared by self-assembly of thiolated polythymine oligonucleotide (5'-SH-T15-3') on the gold electrode via Au-S bonds, and then the surface was passivated with 1-mercaptohexanol solution. The proposed electrode utilizes the specific binding interactions between Hg2+ and thymine to selectively capture Hg2+, thereby reducing the interference from coexistent ions. After exchanging the medium, electrochemical reduction at-0.2V for 60s, voltammetric determination was performed by differential pulse voltammetry using 10mM HEPES (pH 7.2,1M NaClO4) as supporting electrolyte. This electrode showed increasing voltammetric response in the range of 0.2-1nM Hg2+, with a relative standard deviation of 5.32% and a practical detection limit of 60pM. Compared with the conventional stripping approach, the modified electrode exhibits good sensitivity and selectivity, and is expected to be a new type of green electrode.
Chapter Five:Simple and rapid colorimetric mercury sensing assay using mercury-specific DNA-functionalized gold nanoparticles
A new colorimetric assay for Hg2+ based on mercury-specific DNA (MSD)-functionalized gold nanoparticles (AuNPs) is described. The sensing mechanism of the assay is based on thymine-Hg2+-thymine (T-Hg2+-T) chemistry and a unique colloidal stabilization effect associated with conformational change of MSD attached on AuNP surfaces. Upon binding of Hg2+, the surface-tethered MSD undergoes a structure switch and forms hairpin-like structure of T-Hg2+-T complexes. As a result, the Hg2+-induced conformational change significantly enhances the colloidal stability of AuNPs toward salt-induced aggregation. Moreover, the colloidal stability of AuNPs increases as the concentration of Hg2+ increases, accompanied by the color changes of solution from purple to red. The proposed sensor enables the colorimetric detection of Hg2+in the concentration range of 0-10μM Hg2+ ions with a detection limit of 60nM (S/N=3), and allows for the selective discrimination Hg2+ ions from 8 other environmentally and physiologically relevant metal ions.
Chapter Six:Simple and rapid colorimetric assay for mercuric ions based on TCA-capped gold Nanoparticles
A simple, rapid, colorimetric assay for sensing Hg2+ in aqueous solution based on trithiocyanuric acid-capped gold nano-particles (TCA-AuNPs). Trithiocyanuric acid (TCA) is a star-shape trithiol molecule that can spontaneously attach to citrate-capped AuNPs through the displacement of the weakly bound citrate ions and the formation of the Au-S covalent bonds. In the absence of Hg2+, the resulting TCA-AuNPs are dispersed in aqueous solution owing to the high negative charge density of TCA on each AuNP surface. In the presence of Hg2+, the coordination between the mercapto groups of TCA and Hg2+ induced the significant aggregation of TCA-AuNPs via the bridging of neighboring nanoparticles, thereby resulting in a color change that can be observed by the naked eye. Under the optimal conditions, the ration of absorbance (A620/A520) was linearly related to the concentration of Hg2+in the range of 0μM to 1.7μM and the assay allowed detection at levels as low as 50 nM Hg2+. The method is relatively simple and easily operated. The response time upon exposure to Hg2+ is instantaneous. The sensor exhibits highly selective detection of Hg2+ in aqueous solution.
鉴于汞离子对环境和人类健康的危害,发展简单、快速、低成本的汞离子检测技术对生命、环境、医学以及工农业生产等都具有重要的意义。核酸的结构和功能对重金属离子非常敏感,因此,构建基于核酸的汞离子生物传感器引起人们的关注。近年来,有人报道核酸中thymine能与汞离子特异性结合,形成T-Hg2+-T配合物。之后,T-Hg2+-T配合化学成为构建汞离子生物传感器研究的热点。本文主要致力于DNA检测的新型分子信标的设计和基于T-Hg2+-T配位作用的新型汞离子检测技术的构建。具体内容如下：
第一章绪论
首先系统介绍了分子信标的发现及应用研究,包括分子信标结构、工作原理、优化设计及应用现状。接着介绍了基于T-Hg2+-T配位作用的汞离子生物传感器的研究进展。最后阐述了本论文设计思路和研究意义,指出论文的创新之处。
第二章基于电活性-非电活性转换分子信标直接均相检测DNA
本章设计了一种新型的电化学分子信标,即“电活性-非电活性转换分子信标”,直接用于均相检测DNA。该电化学分子信标由一段3’、5’端标记有电化学标记物胭脂红酸,自身能够形成茎-环结构的单链寡核苷酸组成(简称为CAs-MB)。CAs-MB在关闭状态时,两端标记的胭脂红酸单体在茎部互补序列的作用下相互接近,并形成二聚体,从而导致电化学信号的淬灭；与完全互补目标DNA序列杂交时,CAs-MB将发生构象转换,即由自由卷曲的茎-环结构转换为刚性的DNA双链,胭脂红酸二聚体变为单体,从而恢复了胭脂红酸单体的电信号。CAs-MB的电化学信号强度与完全互补目标DNA序列的浓度在0.06-1.4μM范围内成良好线性关系,相关系数为0.998,检出限为30nM。该电化学分子信标能够像传统的荧光分子信标一样有效地识别单碱基错配。CAs-MB有望直接应用于精确地基因分析。
第三章基于非标记分子信标修饰的金胶纳米探针的非交联性聚集比色检测单核苷酸多态性
基于非标记分子信标(Label-free molecular beacon, LMB)修饰的金胶纳米颗粒(AuNPs)的非交联聚集,本章构建了一种新型比色检测单核苷酸多态性的方法。该方法将茎-环结构的分子信标高特异性识别力和金胶纳米颗粒聚集变色的光学特性有机结合在一起,实现了单核苷酸多态性的比色检测。利用金胶纳米的自组装技术将巯基修饰的分子信标探针固定到金胶表面制备分子信标修饰的金胶纳米探针(AuNPs-LMB)。当AuNPs-LMB与不同的目标序列(野生型或突变型)杂交时,金胶表面的LMB的构象由茎-环结构转换为具有一定刚性的双链并引起金胶体系熵、焓的差异性；在适当盐度条件下,AuNPs-LMB对不同目标序列的识别导致金胶纳米颗粒不同程度的聚集,从而实现对SNPs的识别。将该比色传感体系应用于P53基因的单核苷酸多态性的检测,结果令人满意。
第四章基于多胸腺嘧啶寡核苷酸修饰的金电极高灵敏伏安检测汞离子
利用胸腺嘧啶(thymine, T)与汞离子的高亲和识别作用和电化学溶出技术,本章设计了一种具有高灵敏度和高选择性的汞离子生物传感器-多胸腺嘧啶寡核苷酸修饰的金电极即Polythymine oligonucleotide/Au电极(PTO/Au电极)。将一段巯基修饰的polythymine oligonucleotide (5'-SH-T15-3')通过Au-S键自组装到金电极表面上,然后用巯基己醇封闭电极表面即得到PTO/Au电极。利用PTO/Au电极上DNA序列中的碱基T与Hg2+特异性结合的作用选择性把Hg2+富集于电极表面,缓冲液洗涤几次后,在lOmM HEPES (pH7.2, 1M NaClO4)溶液中将富集的Hg2+电化学还原成Hg,然后进行阳极溶出伏安扫描测定汞的氧化电流信号。此修饰电极对Hg2+的响应在0.2-1 nmol/L范围内成良好的线性关系,相关系数为0.9953,检测限达60 pM。另外,此修饰电极在Zn2+、Pb2+等其他六种二价金属离子的存在下并不干扰对Hg2+的检测(nM2+:nHg2+=200:1)。与传统的电化学溶出检测汞离子的方法相比,PTO/Au电极展现了良好的灵敏度和选择性,是一种新型高效的检测汞离子的“绿色”化学修饰电极。
第五章基于汞特异性DNA修饰的金胶纳米探针的比色传感器简便快速检测汞离子
本章制备了一种汞特异性DNA (mercury-specific DNA, MSD)修饰的金胶纳米(Au-MSD)比色探针。该探针通过汞离子操纵修饰在金胶表面的汞特异性DNA的构象转换来调节金胶抵抗盐诱导聚集的能力,从而实现汞离子的简便快速的比色检测。溶液中不存在汞离子时,修饰在金胶表面的汞特异性DNA以随意卷曲的单链构象存在,当再加入一定浓度的MgCl2时,该探针会因为金胶颗粒彼此间的静电排斥力的急剧降低而迅速聚集；相反,溶液中存在汞离子时,汞离子特异性DNA识别汞离子并发生一个由自由卷曲的单链构象向汞介导的“发卡型”刚性双链的转换过程,这些在金胶表面形成的刚性双链大大提高了金胶抵抗盐诱导聚集的能力,致使同样的盐浓度下金胶也不会发生聚集；伴随着上述变化过程,金胶溶液的颜色也由紫红色转变成酒红色,而溶液颜色的变化程度与汞离子的浓度相关。此纳米比色探针对0μM-10μM浓度范围内的汞离子产生良好的响应,检测限为60nM(S/N=3),并应用于实际水样中汞离子的检测。
第六章基于三聚硫氰酸修饰的金胶纳米探针的比色传感系统简便快速检测汞离子
本章利用汞离子的亲巯基性和金胶纳米颗粒的独特光学性质,建立了一种基于三聚硫氰酸(TCA)修饰的金胶纳米探针(TCA-AuNPs)的简单、快速检测汞离子的比色传感方法。表面覆盖有柠檬酸三钠的金胶纳米颗粒与三聚硫氰酸通过配体交换反应制备TCA-AuNPs。TCA分子中的巯基使金胶纳米颗粒表面带有较高密度的负电荷,因而TCA-AuNPs之间相互排斥,所以TCA-AuNPs能够稳定分散在溶液中,溶液颜色呈现酒红色。一旦在TCA-AuNPs溶液中加入一定量的Hg2+, TCA-AuNPs表面的巯基就会与Hg2+配位,导致金胶纳米颗粒的快速聚集,溶液的颜色也由酒红色瞬间变为蓝灰色。金胶纳米颗粒的聚集程度与加入的Hg2+的浓度相关。本章详细探讨了TCA组装密度、不同pH的缓冲介质对TCA-AuNPs检测汞离子的灵敏度的影响。在优化的实验条件下,TCA-AuNPs对Hg2+的吸光度比值响应分别在0-1.7μM(y=0.0568x+0.2312,R2=0.9863)和2.0-6.5μM(y=0.2084x-0.2551,R2=0.9739)范围内呈良好的线性关系,最低检测限为50nM(S/N=3)。当加入的金属离子浓度为70μM时,除Pb2+外,Cd2+等其它9种金属离子均不干扰TCA-AuNPs对Hg2+的检测,而Pb2+的干扰可以通过加入掩蔽剂吡啶-2,6-二甲酸(PDCA)加以消除。TCA-AuNPs制备简单,识别汞离子的速度快,而且具有较高的灵敏度高和较好的选择性。因此,该比色传感系统为快速检测Hg2+提供了一种新途径。
With the completion of the human genome project, there has been a rapid shift in focus from simply collecting and archiving genomic data to utilizing genetic analysis for prediction and discovery. The development and utilization of new quantitative tools for research across disciplinary interfaces will prove vital in achieving these objectives. Molecular beacons (MBs) are ideally suited for and hold great promise in genomics and proteomics. More research is expected for MB applications in mutation detection for a variety of disease diagnostics and disease mechanism studies. Gene expression monitoring in living cells and tissues under different conditions with precise quantitation also provides an avenue for further investigation. The extraordinary target-specific capability along with the availability of different fluorophore-quencher pairs makes MB probes extremely useful for multiple analyte applications as well. These properties also make MBs suited for use in the identification of genetic alleles or particular strains of infectious agents. All of these developments will open the possibility of using easily obtainable and designer DNA molecules for genomics and proteomics studies, for molecular diagnosis of diseases, and for new drug development.
Because of continuing concern over mercury in the environment and its deleterious effects on human health, obtaining new mercury detection methods that are cost-effective, rapid, facile and applicable to the environmental and biological milieus is an important goal. This objective has recently emerged as a focal point in the chemistry and, more broadly, sensing communities. DNA's structure and its functioning in the organism are known to be very sensitive to the influence of heavy metals. So, it is very attractive to use DNA-containing systems, e.g., DNA-based biosensors, to perform heavy metal assays. Recently, it has been reported that mercury ions can selectively bind thymine-thymine pairs in DNA sequences to form T-Hg2+-T complexes. For the moment, thymine-Hg2+-thymine chemistry has been highlighted in the development of Hg2+ sensors because thymine-thymine mismatch shows high selectivity to Hg2+ against many other metal ions.
The goal of the present study is to design and research novel molecular beacon and sensors with high sensitivity and selectivity for Hg2+. This paper combines the excellent characteristics of nanoparticles, the specific recognition of molecular recognition elements and the electrochemical technique. The details are given as follows:
Chapter One:Preface
In this chapter, we review the principles, characteristics of molecular beacon and its application in analytical chemistry field. Several assays based on T-Hg2+-T coordination were introduced. Finally, expounded the aim and the significance, pointed out the research content and the innovation in this paper.
Chapter Two:Electrochemically active-inactive switching molecular beacon for direct detection of DNA in homogenous solution
A new kind of electrochemical molecular beacon was reported, termed "electrochemically active-inactive switching molecular beacon", for direct detection of DNA in homogenous solution. The electrochemical molecular beacon consists of a stable stem-loop oligonucleotide carrying two carminic acid moieties (acting as electrochemical reporter) attached at its termini. In a close form, the electrochemical signal is quenched because two carminic acid moieties are close enough to associate into dimer. In the presence of the complementary DNA target, the electrochemical molecular beacon undergoes a conformational transformation from closed (hairpin) to open (linear) structure, which is associated with an increase in electrochemical signal. We found that the electrochemical molecular beacon is as effective as conventional molecular beacon in signaling the presence of complementary target and discriminating targets that differ by a single nucleotide. The proposed electrochemical molecular beacon has a great potential for investigating the interactions of DNA-protein and developing electrochemical real-time polymerase chain reaction.
Chapter Three:colorimetric detection of SNPs based on label-free molecular beacon modified gold nanoparticles through non-crosslinking aggregation
A new colorimetric approach has been developed for the detection of single nucleotide polymorphisms (SNPs). One label-free molecular beacon was immobilized on the surface of gold nanoparticles through Au-S bonds. The sensitive detection of SNPs was achieved by non-crosslinking aggregation of MB-functionalized gold nanoparticles induced by hybridization of target DNA. The mutant target can be determined in a mixed solution containing 19 times higher concentration of wild target. The allele frequency of 5% was accurately determined in a homogeneous and cost-effective manner.
Chapter Four:Polythymine oligonucleotide-modified gold electrode for voltammetric determination of mercury (Ⅱ) in aqueous solution
Polythymine oligonucleotide (PTO)-modified gold electrode (PTO/Au) was developed for selective and sensitive Hg2+ detection in aqueous solutions. This modified electrode was prepared by self-assembly of thiolated polythymine oligonucleotide (5'-SH-T15-3') on the gold electrode via Au-S bonds, and then the surface was passivated with 1-mercaptohexanol solution. The proposed electrode utilizes the specific binding interactions between Hg2+ and thymine to selectively capture Hg2+, thereby reducing the interference from coexistent ions. After exchanging the medium, electrochemical reduction at-0.2V for 60s, voltammetric determination was performed by differential pulse voltammetry using 10mM HEPES (pH 7.2,1M NaClO4) as supporting electrolyte. This electrode showed increasing voltammetric response in the range of 0.2-1nM Hg2+, with a relative standard deviation of 5.32% and a practical detection limit of 60pM. Compared with the conventional stripping approach, the modified electrode exhibits good sensitivity and selectivity, and is expected to be a new type of green electrode.
Chapter Five:Simple and rapid colorimetric mercury sensing assay using mercury-specific DNA-functionalized gold nanoparticles
A new colorimetric assay for Hg2+ based on mercury-specific DNA (MSD)-functionalized gold nanoparticles (AuNPs) is described. The sensing mechanism of the assay is based on thymine-Hg2+-thymine (T-Hg2+-T) chemistry and a unique colloidal stabilization effect associated with conformational change of MSD attached on AuNP surfaces. Upon binding of Hg2+, the surface-tethered MSD undergoes a structure switch and forms hairpin-like structure of T-Hg2+-T complexes. As a result, the Hg2+-induced conformational change significantly enhances the colloidal stability of AuNPs toward salt-induced aggregation. Moreover, the colloidal stability of AuNPs increases as the concentration of Hg2+ increases, accompanied by the color changes of solution from purple to red. The proposed sensor enables the colorimetric detection of Hg2+in the concentration range of 0-10μM Hg2+ ions with a detection limit of 60nM (S/N=3), and allows for the selective discrimination Hg2+ ions from 8 other environmentally and physiologically relevant metal ions.
Chapter Six:Simple and rapid colorimetric assay for mercuric ions based on TCA-capped gold Nanoparticles
A simple, rapid, colorimetric assay for sensing Hg2+ in aqueous solution based on trithiocyanuric acid-capped gold nano-particles (TCA-AuNPs). Trithiocyanuric acid (TCA) is a star-shape trithiol molecule that can spontaneously attach to citrate-capped AuNPs through the displacement of the weakly bound citrate ions and the formation of the Au-S covalent bonds. In the absence of Hg2+, the resulting TCA-AuNPs are dispersed in aqueous solution owing to the high negative charge density of TCA on each AuNP surface. In the presence of Hg2+, the coordination between the mercapto groups of TCA and Hg2+ induced the significant aggregation of TCA-AuNPs via the bridging of neighboring nanoparticles, thereby resulting in a color change that can be observed by the naked eye. Under the optimal conditions, the ration of absorbance (A620/A520) was linearly related to the concentration of Hg2+in the range of 0μM to 1.7μM and the assay allowed detection at levels as low as 50 nM Hg2+. The method is relatively simple and easily operated. The response time upon exposure to Hg2+ is instantaneous. The sensor exhibits highly selective detection of Hg2+ in aqueous solution.
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