【摘要】：第一部分變色栓菌漆酶1KYA活性位點(diǎn)結(jié)構(gòu)特點(diǎn)及分子對接模型的建立目的:以變色栓菌漆酶-底物復(fù)合物的晶體結(jié)構(gòu)(PDB注冊號(hào):1KYA)為模板,探究1KYA活性位點(diǎn)結(jié)構(gòu)特點(diǎn)與生物功能,并基于分子對接技術(shù),建立變色栓菌漆酶-底物對接模型,揭示分子間相互作用關(guān)系,為后期有關(guān)LMS的研究及數(shù)據(jù)庫篩選提供依據(jù)。方法:以1KYA為模板,利用分子模擬和分子設(shè)計(jì)軟件包MOE(Molecular Operation Environment)的圖形顯示功能,分別從二維(2D)和三維(3D)水平分析漆酶催化氧化活性位點(diǎn)結(jié)構(gòu)特點(diǎn)及其與底物的結(jié)合模式;通過分子對接得到的漆酶-底物對接模型,以確定最佳的分子對接參數(shù)。結(jié)果:1漆酶活性位點(diǎn)的結(jié)構(gòu)特點(diǎn)是,其中的Phe162、Leu164、Asn264、Phe265、Pro391、Gly392、Ala393等氨基酸為中性氨基酸,可與底物產(chǎn)生較強(qiáng)的疏水作用,對底物的結(jié)合起到重要作用,酸性氨基酸Asp206可接受來自底物的質(zhì)子,堿性氨基酸His458為電子受體。2利用分子對接在不同條件將1KYA中的原配體2,5-二甲苯胺對接回活性位點(diǎn),當(dāng)重現(xiàn)出與晶體結(jié)構(gòu)最相近的結(jié)合模式時(shí),確定分子對接最佳參數(shù)設(shè)置為:溫度300K,p H 5.0,分子對接力場設(shè)置為MMFF94x,放置函數(shù)(Placement)設(shè)置為Triangle Mather,打分函數(shù)(Rescoring)設(shè)置為London d G,優(yōu)化函數(shù)設(shè)置(Refinement)設(shè)置為Forcefield。第二部分基于分子對接技術(shù)探究變色栓菌漆酶與氫轉(zhuǎn)移機(jī)制介質(zhì)間的結(jié)合模式和分子機(jī)制目的:為深入探討漆酶與氫轉(zhuǎn)移機(jī)制介質(zhì)間的相互作用,基于分子對接模擬了漆酶與氫轉(zhuǎn)移機(jī)制介質(zhì)間的結(jié)合模式,并在分子水平闡明了漆酶與介質(zhì)的相互作用機(jī)制。方法:基于分子對接技術(shù),構(gòu)建漆酶-介質(zhì)復(fù)合物模型,揭示氫轉(zhuǎn)移機(jī)制介質(zhì)的結(jié)構(gòu)特點(diǎn)及與漆酶作用的分子機(jī)制,為介質(zhì)的結(jié)構(gòu)改造提供方向和思路。結(jié)果:分子對接研究發(fā)現(xiàn)氫轉(zhuǎn)移機(jī)制介質(zhì)與漆酶作用過程中,中性氨基酸與介質(zhì)發(fā)生疏水作用,Asp206作為質(zhì)子受體,通過與介質(zhì)結(jié)構(gòu)中的-OH發(fā)生氫鍵作用,介質(zhì)生成氮氧自由基或苯氧自由基中間體。第三部分基于分子對接技術(shù)探究變色栓菌漆酶與電子轉(zhuǎn)移機(jī)制介質(zhì)間的結(jié)合模式和分子機(jī)制目的:采用分子對接方法探究電子轉(zhuǎn)移機(jī)制介質(zhì)與漆酶的結(jié)合模式和作用機(jī)制。方法:基于分子對接技術(shù),構(gòu)建漆酶-介質(zhì)復(fù)合物模型,揭示電子轉(zhuǎn)移機(jī)制介質(zhì)與漆酶作用的分子機(jī)制,為介質(zhì)的結(jié)構(gòu)改造提供方向和思路。結(jié)果:電子轉(zhuǎn)移機(jī)制介質(zhì)與漆酶作用過程中,中性氨基酸與介質(zhì)發(fā)生疏水作用,His458作為電子受體,介質(zhì)失去電子轉(zhuǎn)化為陽離子中間體。第四部分漆酶-介質(zhì)-有機(jī)磷毒物三元復(fù)合物體系的分子機(jī)制研究目的:本研究通過分子模擬技術(shù)探究LMO作用模式,為后期漆酶與介質(zhì)的理性設(shè)計(jì),進(jìn)一步提高LMS的作用范圍和催化效率奠定理論基礎(chǔ)。方法:基于分子對接技術(shù),構(gòu)建LMO模型,揭示三元體系分子間的結(jié)合模式和作用機(jī)制;基于分子動(dòng)力學(xué)方法模擬LMO模型相互作用過程中受體Cα原子的變化,考察三元體系的穩(wěn)定性和動(dòng)態(tài)研究LMS對有機(jī)磷毒物的降解機(jī)制。結(jié)果:在LMO中,介質(zhì)結(jié)合于漆酶活性位點(diǎn)內(nèi)部,與Asp206產(chǎn)生氫鍵作用,與內(nèi)部中性氨基酸產(chǎn)生疏水作用和π-π堆積作用;介質(zhì)在以上作用力的共同作用下生成介質(zhì)中間體,進(jìn)而與結(jié)合于漆酶活性位點(diǎn)外緣的有機(jī)磷毒物發(fā)生相互作用;分子動(dòng)力學(xué)模擬發(fā)現(xiàn),當(dāng)三元復(fù)合物達(dá)到穩(wěn)定時(shí)漆酶構(gòu)象發(fā)生了突變,其中電子受體His458靠近了介質(zhì)遠(yuǎn)離了Ⅰ型銅離子(T1Cu),有利于介質(zhì)與漆酶之間的電子傳遞,且造成T1Cu的“缺電子特性”,從而氧化電勢升高,電子傳遞速率加快。第五部分構(gòu)建具有木質(zhì)素降解產(chǎn)物基本結(jié)構(gòu)單元的小分子數(shù)據(jù)庫目的:通過文獻(xiàn)檢索搜集更多具有木質(zhì)素降解產(chǎn)物基本結(jié)構(gòu)單元的小分子化合物,構(gòu)建具有木質(zhì)素降解產(chǎn)物基本結(jié)構(gòu)單元的小分子數(shù)據(jù)庫(Molecular with Basic unit of Lignin degradation products Database,MBLD),從中挖掘新介質(zhì)。方法:對文獻(xiàn)報(bào)道的具有木質(zhì)素降解產(chǎn)物結(jié)構(gòu)單元的小分子化合物進(jìn)行總結(jié),利用MOE數(shù)據(jù)庫模塊建立用于挖掘新介質(zhì)的MBLD。結(jié)果:通過文獻(xiàn)檢索和整理,收集到27個(gè)具有木質(zhì)素降解產(chǎn)物結(jié)構(gòu)單元的化合物,構(gòu)建了MBLD,該數(shù)據(jù)庫包含了化合物的2D和3D結(jié)構(gòu)信息,為后續(xù)的數(shù)據(jù)庫篩選提供了化學(xué)信息學(xué)基礎(chǔ)。第六部分基于分子對接和分子相似性搜索數(shù)據(jù)庫篩選漆酶新介質(zhì)目的:通過對MBLD和中藥化學(xué)數(shù)據(jù)庫(Traditional Chinese Medicine Database,TCMD)進(jìn)行篩選,從中發(fā)現(xiàn)漆酶新介質(zhì)。方法:綜合運(yùn)用分子對接和分子相似性搜索對MBLD和購買的中藥化學(xué)數(shù)據(jù)庫(Traditional Chinese Medicine Database,TCMD)進(jìn)行篩選并對篩選所得化合物進(jìn)行結(jié)構(gòu)優(yōu)化和理論驗(yàn)證,以發(fā)現(xiàn)漆酶新介質(zhì)。結(jié)果:基于分子對接和分子相似性搜索分別對MBLD和TCMD中近一萬個(gè)化合物進(jìn)行篩選,根據(jù)結(jié)合模式分析優(yōu)先篩選出26個(gè)潛在的漆酶新介質(zhì),這些化合物與常見的天然介質(zhì)在結(jié)構(gòu)上十分相似,差異主要體現(xiàn)在取代基的種類和位置上。第七部分漆酶介質(zhì)分子的結(jié)構(gòu)改造與理論驗(yàn)證目的:本研究以紫丁香醇和丁香酸甲酯為模板,通過改變鄰位取代基嘗試不同的結(jié)構(gòu)改造方案并確定鄰位取代基的最佳改造方案,并進(jìn)行理論驗(yàn)證。方法:基于分子對接方法,將改造后的分子與漆酶對接,進(jìn)行理論驗(yàn)證。結(jié)果:利用分子模型和分子對接技術(shù),探明了介質(zhì)與漆酶活性位點(diǎn)結(jié)合與反應(yīng)的結(jié)構(gòu)特點(diǎn)。結(jié)果表明,介質(zhì)酚羥基鄰位取代基可保持與漆酶作用過程中介質(zhì)構(gòu)象的穩(wěn)定,鄰位取代基給電子能力可增強(qiáng)介質(zhì)中間體的穩(wěn)定性;介質(zhì)酚羥基對位取代基的吸電子性有利于加強(qiáng)與Phe265間的π-π堆積作用,但對位取代基吸電性過強(qiáng)反而不利于提高介質(zhì)反應(yīng)活性及苯氧自由基中間體的穩(wěn)定性。第八部分新介質(zhì)用于漆酶-介質(zhì)體系降解有機(jī)磷毒物的理論研究目的:將丁香亭和去氫二異丁香酚及其結(jié)構(gòu)改造后的新化合物用于LMS降解有機(jī)磷毒物,進(jìn)一步在理論層面說明丁香亭和去氫二異丁香酚及其結(jié)構(gòu)改造后的化合物成為新介質(zhì)的可能性。方法:基于分子動(dòng)力學(xué)方法,驗(yàn)證新介質(zhì)降解有機(jī)磷毒物的效果。結(jié)果:從虛擬篩選所得化合物中,選擇丁香亭和去氫二異丁香酚作為研究對象,根據(jù)機(jī)制研究結(jié)果和化學(xué)結(jié)構(gòu)理論對兩者進(jìn)行結(jié)構(gòu)改造,原分子結(jié)構(gòu)中酚羥基鄰位取代基改造為兩個(gè)丙烯酸基,將改造后的新化合物放于LMO體系進(jìn)行驗(yàn)證,新化合物均能穩(wěn)定存在于LMO體系,且與漆酶之間相互作用力種類和數(shù)目均有增多,結(jié)合自由能更低,與漆酶結(jié)合更加穩(wěn)定。結(jié)論:1漆酶與介質(zhì)相互作用過程中,漆酶活性位點(diǎn)的中性氨基酸主要與介質(zhì)產(chǎn)生疏水作用,穩(wěn)定介質(zhì)的結(jié)合構(gòu)象,Asp206可作為質(zhì)子受體,His458為電子受體。2介質(zhì)分子結(jié)構(gòu)中,酚羥基鄰位取代基可保持與漆酶作用過程中介質(zhì)構(gòu)象的穩(wěn)定,且其給電子效應(yīng)可增強(qiáng)介質(zhì)中間體的穩(wěn)定性;酚羥基對位取代基的吸電子性可加強(qiáng)與Phe265間的π-π堆積作用,但吸電性過強(qiáng)反而不利于提高介質(zhì)反應(yīng)活性及介質(zhì)中間體穩(wěn)定性。3在LMO中,介質(zhì)結(jié)合于漆酶活性位點(diǎn)內(nèi)部,有機(jī)磷毒物結(jié)合于漆酶活性位點(diǎn)外緣,漆酶通過介質(zhì)中間體降解有機(jī)磷毒物。在LMO達(dá)到穩(wěn)定時(shí)漆酶構(gòu)象發(fā)生突變,該構(gòu)象變化提高了漆酶氧化電勢,促進(jìn)了漆酶與介質(zhì)間的電子傳遞,更有利于有機(jī)磷毒物的降解。4從MBLD和TCMD中優(yōu)先選出26個(gè)先導(dǎo)物,綜合結(jié)合模式分析、分子結(jié)構(gòu)特點(diǎn)、結(jié)合自由能和氫傳遞距離等因素,發(fā)現(xiàn)丁香亭和去氫二異丁香酚最具成為漆酶新介質(zhì)的潛力,作為后期研究重點(diǎn)。5對常見天然介質(zhì)酚羥基鄰位取代基進(jìn)行結(jié)構(gòu)改造發(fā)現(xiàn),將其改造為兩個(gè)丙烯酸基后與漆酶結(jié)合效果最佳。鄰位取代基為丙烯酸基的新化合物與漆酶結(jié)合構(gòu)象更穩(wěn)定,且避免了不利因素分子內(nèi)氫鍵的產(chǎn)生。6對丁香亭和去氫二異丁香酚進(jìn)行結(jié)構(gòu)改造,新化合物能穩(wěn)定存在于三元復(fù)合物中,且結(jié)合模式較改造前更好,初步驗(yàn)證了改造的合理性,預(yù)測新化合物作為漆酶介質(zhì)催化效率會(huì)有明顯提高。
[Abstract]:The first part is about the structural characteristics of 1KYA active site and the establishment of molecular docking model of the laccase-substrate complex of Thrombococcus discolor. Methods: Using 1KYA as a template and using the graphical display function of Molecular Operation Environment (MOE), the structure characteristics of laccase catalytic oxidation sites were analyzed at two-dimensional (2D) and three-dimensional (3D) levels, respectively. Results: 1. The structure of laccase sites was characterized by the neutral amino acids such as Phe162, Leu164, Asn264, Phe265, Pro391, Gly392 and Ala393, which could produce strong hydrophobic interaction with the substrate. Acidic amino acid Asp206 accepts protons from substrates, and basic amino acid His458 is an electron acceptor. 2 Docking of proligand 2,5-dimethylaniline in 1KYA to the active site under different conditions is used to determine the optimal molecular docking when the most similar binding mode is reproduced. The parameters are as follows: temperature 300K, P H 5.0, molecular butt relay field MMFF94x, placement Triangle Mather, Rescoring London DG and Refinement Forcefield. The second part explores the mechanism between chameleon laccase and hydrogen transfer media based on molecular butt technology. The binding modes and molecular mechanisms of laccase and hydrogen transfer mediators were investigated. The binding modes between laccase and hydrogen transfer mediators were simulated based on molecular docking, and the interaction mechanism between laccase and mediator was clarified at the molecular level. Results: Molecular docking studies showed that neutral amino acids had hydrophobic interaction with laccase, Asp206 acted as a proton acceptor through the interaction with laccase. In the third part, based on the molecular docking technology, the binding mode and molecular mechanism between the laccase and the electron transfer mechanism medium of T. chromotropica were explored. The binding mode and interaction between the electron transfer mechanism medium and the laccase were explored by the molecular docking method. Mechanisms. Methods: Based on the molecular docking technique, a laccase-mediator complex model was constructed to reveal the molecular mechanism of the interaction between the electron transfer mechanism medium and laccase, and to provide directions and ideas for the structural modification of the medium. Part IV. Molecular mechanism of laccase-mediator-organophosphorus toxicant ternary complex system. Objective: This study explored the mode of action of LMO by molecular simulation technology, laying a theoretical foundation for the rational design of laccase and mediator, and further improving the range of action and catalytic efficiency of LMS. METHODS: Based on the molecular docking technique, a LMO model was constructed to reveal the binding mode and interaction mechanism of the ternary system. The changes of receptor C alpha atoms during the interaction of the LMO model were simulated by molecular dynamics method, and the stability and dynamics of the ternary system were investigated. Medium bound to the site of laccase activity, hydrogen bonding with Asp206, hydrophobic interaction with internal neutral amino acids and pion-pion stacking; Medium formed medium intermediates under the combined action of the above forces, and then interacted with organic phosphorus poisons bound to the outer edge of laccase activity site; Molecular dynamics simulation hair Now, when the ternary complex stabilized, the conformation of laccase changed. The electron acceptor His458 was close to the medium and away from type I copper ion (T1Cu), which was beneficial to the electron transfer between the medium and laccase, and resulted in the "electron deficiency" of T1Cu, thus increasing the oxidation potential and accelerating the electron transfer rate. OBJECTIVE: To collect more small molecular compounds with basic structural units of lignin degradation products and construct a small molecular database (MB) with basic structural units of lignin degradation products. METHODS: Small molecular compounds with structural units of lignin degradation products reported in the literature were summarized, and MBLD for mining new media was established by using MOE database module. The database contains 2D and 3D structural information of compounds, which provides a chemical informatics basis for subsequent database screening. Part VI Screening of new laccase media based on molecular docking and molecular similarity search database Objective: To screen MBLD and Traditional Chinese Medicine Database (TCMD). Methods: MBLD and TCMD were screened by molecular docking and molecular similarity search, and the structures of the compounds were optimized and verified theoretically to find new laccase media. Similarity search screened nearly 10,000 compounds in MBLD and TCMD respectively. According to the binding pattern analysis, 26 potential laccase mediators were screened out. These compounds were very similar to the common natural media in structure, and the differences were mainly reflected in the types and positions of substituents. Part VII: Structural modification of laccase mediators In this study, syringol and methyl eugenolate were used as templates to try different structural modification schemes by changing the ortho-substituents and to determine the best modification scheme of the ortho-substituents. Methods: Based on the molecular docking method, the modified molecules were docked with laccase to verify the theory. The results showed that the phenolic hydroxyl ortho-substituents could maintain the stability of the medium conformation during the interaction with laccase, and the electron donor ability of the ortho-substituents could enhance the stability of the medium. The electron absorption of the group is beneficial to the enhancement of the pi-pi stacking with Phe 265, but the strong electro-absorption of the p-substituent is not conducive to the enhancement of the reactivity of the medium and the stability of the phenoxy free radical intermediates. Part VIII Theoretical study on the degradation of organophosphorus poisons by laccase-medium system The degradability of organophosphorus poisons in LMS by carvol and its new compounds after structural modification was further explained theoretically. METHODS: Based on molecular dynamics method, the degradability of organophosphorus poisons in the new media was verified. Among the selected compounds, eugenol and dehydrodiisoeugenol were selected as the research objects. According to the results of mechanism research and chemical structure theory, the structures of the two compounds were reconstructed. The ortho-substituents of phenolic hydroxyl groups in the original molecular structure were reconstructed into two acrylic groups, and the new compounds were put into LMO system to verify the stability of the new compounds. The type and number of interaction forces between laccase and laccase increased, the binding free energy was lower, and the binding with laccase was more stable. CONCLUSION: 1 In the process of interaction between laccase and medium, the neutral amino acids of laccase activity site mainly produced hydrophobic interaction with medium, and the binding conformation of stable medium was stable, Asp206 could be used as proton. Receptor, His458 is the electron acceptor. In the molecular structure of the medium, the phenolic hydroxyl ortho-substituent can maintain the stability of the medium conformation during the interaction with laccase, and its electron-donating effect can enhance the stability of the medium. The electron-absorbing property of the phenolic hydroxy ortho-substituent can enhance the pion-pion stacking interaction with Phe 265, but the strong electro-absorbing property does not. In LMO, the medium is bound to the interior of the laccase activity site, the organophosphorus poison is bound to the outer edge of the laccase activity site, and the laccase degrades the organophosphorus poison through the medium. When the LMO is stable, the laccase conformation mutates, which improves the laccase oxidation potential and promotes the laccase oxidation. Electron transfer between laccase and medium is more conducive to the degradation of organophosphorus poisons. 4 Twenty-six precursors were selected from MBLD and TCMD. Combined with mode analysis, molecular structure characteristics, free energy and hydrogen transfer distance, it was found that eugenol and dehydrodiisoeugenol had the most potential to be new laccase media, and could be used as a new laccase in the later stage. 5. The structure modification of phenolic hydroxyl ortho-substituents in common natural media showed that the ortho-substituents had the best binding effect with laccase. New compounds with ortho-substituents of acrylic group had more stable binding conformation with laccase and avoided the formation of intramolecular hydrogen bonds. The structure of isoeugenol was reconstructed, and the new compound could exist stably in the ternary complex, and the binding mode was better than before. The rationality of the modification was preliminarily verified. It was predicted that the catalytic efficiency of the new compound as laccase medium would be significantly improved.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：Q55

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相關(guān)期刊論文 前10條

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