光谱法和分子对接技术研究FTO蛋白与小分子的相互作用

发布时间：2018-05-26 04:29

本文选题：FTO蛋白 + 小分子　；参考：《郑州大学》2017年硕士论文

【摘要】：研究蛋白质与小分子配体的相互作用,不仅可以探究小分子对蛋白质结构和功能的影响,还有助于了解小分子在体内的分布、吸收、代谢等信息,为新药的设计、开发以及药物分子结构的改造提供参考。FTO(The fat mass obesity associated)基因是第一个被确认的肥胖易感基因,它高度表达于下丘脑、骨骼肌、脂肪等组织器官,可以通过控制食物摄入和能量消耗来影响肥胖。FTO基因编码的蛋白质是一种核酸去甲基化酶,它在哺乳动物体内的主要作用是调节能量平衡。因此,研究FTO蛋白与小分子的相互作用对于治疗肥胖相关药物的研发具有重要意义。荧光和紫外-可见吸收光谱法,具有操作简单、灵敏度高和分析速度快等优点,可以同时给出小分子与蛋白质相互作用的猝灭机理、结合常数、作用力类型以及蛋白质的构象变化等信息。分子对接技术可以形象地呈现出小分子与蛋白质相互作用的结果。本论文综合运用光谱分析法和分子对接技术对六组不同类型的小分子与FTO蛋白的相互作用进行了研究。论文包括以下七个部分的内容:第一章概述了小分子与蛋白质相互作用的研究意义,并对FTO作了简单介绍。综述了常见的研究方法和相互作用的研究内容。第二章研究了FTO与三种黄酮类化合物(槲皮素,芹菜素,柚皮素)的相互作用。光谱法的研究结果表明这三种化合物对FTOQg源荧光的猝灭属于静态猝灭;槲皮素与FTO结合的作用力主要为疏水和静电作用,而芹菜素和柚皮素与FTO之间的作用力主要为疏水作用和氢键;在三个化合物中,槲皮素与FTO的结合能力最强,这可能与其结构中含有较多的羟基有关;柚皮素可以使色氨酸残基微环境的极性增加。第三章研究了FTO与六种喹唑啉酮衍生物的相互作用。结果表明,Q1、Q2、Q3和Q4可以使FTO的Qg源荧光发生猝灭,且猝灭机制为静态猝灭,而Q5和Q6并不能使其发生猝灭,我们认为这可能与分子结构中的取代基有关;分子的空间位阻是影响前四种衍生物与FTO结合强弱的主要因素,位阻越小越有利于结合;疏水作用力在它们的结合过程中发挥了主要作用;Q2和Q4可以使色氨酸残基的微环境极性发生改变。第四章研究了FTO与四种Taiwaniaquinones(两组同分异构体)的相互作用。结果表明,四种Taiwaniaquinones引起FTO荧光猝灭的机制均为静态猝灭;两组同分异构体与FTO结合能力的强弱与分子中的共轭体系有关;T1能使色氨酸的微环境发生变化;疏水作用力在结合过程中发挥了主要作用。第五章研究了FTO与四种2-氨基色酮化合物的相互作用。研究表明,四种2-氨基色酮化合物均能够导致FTO发生荧光猝灭,且猝灭机理为静态猝灭;分子的空间位阻是影响化合物与FTO结合强弱的主要因素;疏水作用力在结合过程中发挥了主要作用;色氨酸和酪氨酸残基所处微环境的极性基本未发生改变。第六章对FTO和三种核苷类似物的相互作用进行了研究。结果表明,三种核苷类似物引起FTO荧光猝灭的机理均为形成复合物的静态猝灭;N1与FTO的结合以疏水作用为主,N2主要依靠氢键和范德华力,N3则以氢键为主;三种核苷类似物中,N1对FTO的猝灭和结合能力最强,这可能与N1分子中含有非极性的苯环有关;同步荧光的结果表明N2和N3可以导致色氨酸微环境的极性发生变化。第七章研究了己烯雌酚(DES)与FTO的相互作用。DES对FTO荧光猝灭的机理为静态猝灭;疏水作用在复合物的形成过程中发挥了主要作用;酪氨酸和色氨酸的微环境基本未发生改变。
[Abstract]:The study of the interaction between protein and small molecular ligands can not only explore the effects of small molecules on protein structure and function, but also help to understand the distribution, absorption and metabolism of small molecules in the body, and for the design of the new drug, the development of the molecular structure of the drug, and the reference.FTO (The fat mass obesity associated) gene. The first identified obesity susceptibility gene, which is highly expressed in the hypothalamus, skeletal muscle, fat and other tissues and organs, can affect the protein encoded by the obesity.FTO gene by controlling food intake and energy consumption as a nucleic acid demethylation enzyme. Its main role in mammals is to regulate energy balance. Therefore, the study of FTO eggs The interaction between white and small molecules is of great significance for the research and development of obesity related drugs. Fluorescence and UV visible absorption spectroscopy have the advantages of simple operation, high sensitivity and rapid analysis, and can simultaneously give out the quenching mechanism of interaction between small molecules and proteins, binding constants, type of force and protein. The interaction between small molecules and protein can be presented image by molecular docking technique. The interaction of six different types of small molecules with FTO protein is studied in this paper. The paper includes the contents of the next seven parts: the first chapter is summarized. The research significance of the interaction of small molecules with protein and a brief introduction to FTO. The common research methods and research contents of interaction are reviewed. The second chapter studies the interaction between FTO and three flavonoids (quercetin, apigenin, naringenin). The results of spectroscopic studies show that these three compounds are fluorescent to the source of FTOQg. The interaction between quercetin and FTO is mainly hydrophobic and electrostatic, while the interaction between apigenin and naringenin and FTO is mainly hydrophobic and hydrogen bonds; in the three compounds, quercetin has the strongest binding capacity with FTO, which may be related to the many hydroxyl groups in the structure; naringenin can be used. The polarity of the tryptophan residues microenvironment is increased. The interaction between FTO and six quinazolinone derivatives is studied in the third chapter. The results show that Q1, Q2, Q3 and Q4 can quench the fluorescence of Qg source in FTO, and the quenching mechanism is static quenching, while Q5 and Q6 can not make it quenched. We think this may be with the substituents in the molecular structure. The space hindrance of the molecules is the main factor affecting the combination of the first four derivatives with FTO, and the smaller the steric resistance is more beneficial to the binding; the hydrophobic forces play a major role in their binding process; Q2 and Q4 can make the microenvironmental polarity of the tryptophan residues change. The fourth chapter studies the FTO and the two groups (two groups are the same. The interaction of the isomers. The results show that the mechanism of the four kinds of Taiwaniaquinones causing FTO fluorescence quenching is static quenching; the strength of the two isomers and the FTO binding ability is related to the conjugated system in the molecule; T1 can change the microenvironment of tryptophan, and the hydrophobic forces play a major role in the process of binding. Fifth The interaction between FTO and four 2- amino chroone compounds was studied in this chapter. The study shows that the four 2- amino chroone compounds can cause fluorescence quenching of FTO, and the quenching mechanism is static quenching; the molecular space hindrance is the main factor affecting the combination of compound and FTO, and the hydrophobic interaction exerts the main action during the binding process. The polarity of the microenvironment in which tryptophan and tyrosine residues were used basically did not change. In the sixth chapter, the interaction between FTO and three nucleoside analogues was studied. The results showed that the mechanism of FTO fluorescence quenching caused by three nucleoside analogues was the static quenching of the complex, and the combination of N1 and FTO was mainly hydrophobic, and N2 mainly depended on it. By hydrogen bonds and van Edward force, N3 is the hydrogen bond, and the quenching and binding ability of N1 to FTO is the strongest in the three nucleoside analogues. This may be related to the non polar benzene ring in the N1 molecule. The results of synchronous fluorescence show that N2 and N3 can lead to the change in the polarity of the tryptophan microenvironment. The seventh chapter studies the phase of diethylstilbestrol (DES) and FTO. The mechanism of FTO fluorescence quenching is static quenching, and the hydrophobic effect plays a major role in the formation of the complex, and the microenvironment of tyrosine and tryptophan has not changed basically.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O657.3;TQ460.1

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