本文關鍵詞：甲型H1N1流感病毒毒株的分子特征及功能分析預測　出處：《山東大學》2010年碩士論文　論文類型：學位論文

  更多相關文章： 甲型流感病毒 H1N1 血凝素 神經(jīng)氨酸酶 結(jié)構(gòu)生物信息學分析

【摘要】： 2009年4月,起源于墨西哥的新型流感引起人們一片恐慌,在短短幾周之內(nèi),新型流感病毒就迅速地蔓延到了全世界,2009年6月11日,世界衛(wèi)生組織將全球流感大流行警告級別提升至最高等級第六級,中國乃至山東省都是此次流感的重災區(qū),影響人們的正常工作生活。 此次爆發(fā)的流感病毒為一類新型流感病毒,本論文利用結(jié)構(gòu)生物信息學的方法系統(tǒng)分析了山東省毒株的分子特征,并對其功能進行了分析預測。通過分子發(fā)育分析,山東省毒株為血凝素(HA)1型,神經(jīng)氨酸酶(NA)1型毒株。毒株的基因組來源人、豬、禽流感的遺傳物質(zhì),是一個四重排甲型流感病毒。其HA、NP和NS基因來源于H1N1亞型經(jīng)典豬流感毒株,NA和MP基因來源于H1N1亞型禽源豬流感毒株。PA和PB2基因來源于不同亞型的禽流感病毒,PBl基因來源于季節(jié)性H3N2亞型人流感病毒。雖然新甲型H1N1流感病毒8個基因片段所形成的進化樹各不相同,但仍然存在一些共性：4株新甲型H1N1流行病毒株A/Mexico/4486/2009;A/California/04/2009; A/Beijing/3/2009 (H1N1)和A/Shandong/1/2009都聚在一起,形成獨立的進化支,并且以高Bootstrap值支持。說明09年新甲型H1N1流感病毒有共同的進化祖先,H1N1流感病毒在流行擴散過程中沒有顯著變異。對其血凝素蛋白的結(jié)構(gòu)、表面電勢分析及分子對接分析表明該甲型H1N1流感病毒的受體結(jié)合位點與典型的人流感病毒的氨基酸完全一致,這意味著新型甲型H1N1流感病毒蛋白的受體結(jié)合特異性完全符合感染人類的要求,具備人傳播人的分子基礎的。這也在一定程度上解釋了甲型此次H1N1流感病毒只在人與人之間傳播,極少見人與豬之間傳播的現(xiàn)象。 通過該毒株HA蛋白的糖基化、脂化位點分析,發(fā)現(xiàn)將毒株的HA蛋白的糖基化位點僅有27位,28位,40位,104位,286位,304位,及498位較相關其它季節(jié)性流感病毒變少,脂化位點與二硫鍵位點未發(fā)生變化。山東省毒株具有較少糖基化位點,這暗示該甲型流感病毒應具有較強的致病力。通過基于序列與基于結(jié)構(gòu)的抗原決定簇分析,發(fā)現(xiàn)山東省毒株的HA蛋白的抗原決定簇主要位于蛋白的頭部,相對澳大利亞毒株,抗原決定簇Cal區(qū)222位發(fā)生突變(Lys→Arg),相對于2009年美洲區(qū)域的毒株未發(fā)生明顯變化,因此其于世衛(wèi)組織提供的毒株生產(chǎn)的相關疫苗應該是有效的。通過對NA蛋白結(jié)構(gòu)的預測分析,表明相對于其它季節(jié)性流感的NA,此次NA突變的氨基酸位點主要位于活性中心以外的分子表面,未發(fā)生NA酶的活性中心,所以針對NA蛋白的相關藥物應該是有效的。 本文通過對山東省毒株的基因序列、蛋白質(zhì)序列、蛋白質(zhì)結(jié)構(gòu)、分子表面性質(zhì)、分子對接分析、抗原決定簇、藥物作用靶位的快速分析,初步建立了快速定型、分析、預測的結(jié)構(gòu)生物信息學方法,該對甲型流感病毒的防控應該具有借鑒與參考意見,特別是對當前山東省當前的疾病防控的基礎與形勢,本文建立的方法應該會使得相應防控技術由依靠經(jīng)驗轉(zhuǎn)化理性化,特別是隨著新一代低成本高通量測序技術的發(fā)展,相信結(jié)構(gòu)生物信息學方法將會成為主流技術指導新形勢下大流行疾病的防控。
[Abstract]:In April 2009, the new flu originated in Mexico caused people to panic, in a few weeks, the new swine flu virus is spreading rapidly around the world, in June 11, 2009, the WHO will be a global influenza pandemic alert level raised to the highest level sixth, Chinese and Shandong province are the hardest hit by the flu, affecting people's normal working life.
The outbreak of the influenza virus is a new type of influenza virus, method of system by making use of the structural bioinformatics analysis of the molecular characteristics of strains in Shandong Province, and analyzed its function prediction. By molecular phylogenetic analysis, Shandong province strain hemagglutinin (HA) type 1, neuraminidase (NA) type 1 strains. The genome of the strains from human, swine and avian influenza genetic material, is a rearrangement of four influenza A virus. The HA, NP and NS gene from subtype H1N1 of classical swine flu strain, NA source and MP gene from avian H1N1 Subtype Swine influenza virus strain.PA and PB2 gene from different subtypes avian influenza virus, PBl gene derived from seasonal human influenza virus subtype H3N2. Although the phylogenetic tree formed by the new H1N1 influenza virus 8 gene fragments of each are not identical, but there are still some similarities: 4 strains of new influenza H1N1 epidemic strains A/Mexico/4486/200 9; A/California/04/2009; A/Beijing/3/2009 (H1N1) and A/Shandong/1/2009 were clustered together, forming an evolutionary independent branch, and support with high Bootstrap value. 09 years of the new H1N1 influenza virus have a common evolutionary ancestor, H1N1 influenza virus has no significant variation in the popular diffusion process. Structure of the hemagglutinin protein, surface potential analysis and molecular docking analysis showed that the H1N1 influenza virus receptor binding sites of amino acids and typical human influenza virus completely consistent, which means that the new H1N1 influenza virus protein receptor binding specificity in full compliance with the requirements of human infection, and has the molecular basis of human communication. This partly explains the H1N1 influenza virus only spread between people, but seldom spread between human and swine.
The glycosylation of the strains of HA protein, lipid analysis sites, found that the glycosylation site strain HA protein only 27, 28, 40, 104, 286, 304, and 498 than other seasonal influenza viruses become less lipid sites and two sulfur the key points are not changed. Shandong province strains have fewer glycosylation sites, suggesting that the influenza virus with strong pathogenicity. Based on sequence and structure based antigen determinants analysis, found that the epitopes of HA protein in Shandong province were mainly located in the head of Australia protein, virus antigen determinant Cal 222 mutations (Lys, Arg), compared with the 2009 American regional strains did not change significantly, so it provides from who strains vaccine should be effective. Through the prediction of NA protein structure analysis showed that, compared with the For other seasonal influenza NA, the amino acid site of NA mutation is mainly located outside the surface of the active center, and there is no active center of NA enzyme. Therefore, NA related drugs should be effective.
The gene sequence of Shandong strain protein sequence, protein structure, molecular surface properties, molecular docking analysis, antigenic determinant, rapid analysis of target drugs, initially established a fast setting, structure analysis, bioinformatics method, the prevention and control of influenza A virus should have reference opinions, especially based on the current situation in Shandong province and the disease prevention and control, this method should make the corresponding prevention and control technology of rational transformation by relying on experience, especially with the development of a new generation of low cost and high throughput sequencing technology, believe that structural bioinformatics methods will become the mainstream technology of pandemic diseases prevention and control guidance under the new situation.

【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2010
【分類號】：R373

【引證文獻】

相關期刊論文 前1條

1 朱廣蕊;潘耀謙;夏銀可;劉興友;;甲型H1N1流感病毒致病機理研究進展[J];動物醫(yī)學進展;2011年08期

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本文編號：1412921