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题名	P53蛋白质的末端二级结构预测及核心区点突变模拟研究
作者	张彦
学位类别	博士
答辩日期	1999
授予单位	中国科学院云南天文台
授予地点	昆明
导师	刘次全
关键词	mRNA 二级结构 二级结构预测 p53 蛋白质 分子动力学
中文摘要	根据刘次全研究员等发现的蛋白质与其编码mRNA二级结构之间可能存在着二级结构单元数目间的对应关系，首次尝试参照p53蛋白质N/C末端的编码mRNA二级结构预测p53蛋白质N/C末端相应的二级结构。预测结果显示，在p53蛋白质N端1－93残基肽段可能存在四个α螺旋结构（14-26，38-46，51-56，68-70aa）。在p53蛋白质C端单体聚合区以后的区域可能存在另外两个α螺旋（368-373，381-388aa）。在p53蛋白质N/C端未知二级结构的预测区域内没有发现β片层结构。这些预测结果与法国蛋白质生物和化学研究所（IBCP）多重序列联配蛋白质二级结构预测方法对照（其准确率为73.20％左右），结果基本一致。在此工作基础上，将p53蛋白质N/C端预测的二级结构在SGI-INDIGO~2工作站上分别构建出三维构象模型。与分子生物学研究的资料对照，这两个模型较好的解释了p53蛋白质N/C末端特定的生物功能在三维结构上的相应特点。此外，在SGI－INDIGO~2工作站上，首次选择和利用p53蛋白质突变研究近十年积累的大量资料，以及p53蛋白质核心区三维晶体结构数据资料，对Arg175，Arg249，和Arg248三个p53蛋白质高频率突变点的十种不同的残基替换做了分子动力学研究。结果发现，p53蛋白质核心区在经历 12ps的分子动力学过程后，其三维构象基本保持不变，表明p53核心区不仅在生化方面具有抗蛋白酶分解的高度稳定性，在分子力学方面也具有很高的稳定性。与此相反，R175和R249两个突变热点上的各类残基替换型核心区结构，以及R248 的突变热点上的部分残基替换型结构，在经历了同样条件的分子动力学过程之后，其DNA结合面全部丧失了原有的机能构象，有的甚至使核心区β片层结构形成的三明治骨架系统发生散解，核心区原有的疏水核心松散暴露，整个p53核心区正常构象趋于解体。这些动力学模型从新的角度，直观的充实了以往分子生物学研究发现的p53蛋白质野生型与突变型之间，不同生化特性和蛋白质免疫抗原特征存在的三维构象基础。
英文摘要	It is the first time to predict the secondary structures of N/C terminuses of p53 protein by referring the secondary structures of their encoding mRNA secondary structures. This work was based on the find that there is a unit numbers corespondent relationship probably existing between the secondary structures of protein and its encoding mRNA which is advanced by Prof. Liu Ci-quan et al in 1998. The result of prediction shows there are four α helix (14-16, 38-46, 51-56, 68-70aa) in the ne-terminal region, and another tow α helix (368-373, 381-388aa) in c-terminal region of p53 protein, no β sheet was found in this two predicted region. These prediction results conformed with the other four methods of protein secondary structure prediction based on the multiple sequence alignment (accuracy = 73.20%) performed by France Institute of Biology and Chemistry of Protein (IBCP). Furthermore, the predicted protein secondary structures were built up into two models of 3-D conformations in SGI-INDIGO~2 workstation. Referring with the experimental data, these models better expound the relations among those biological function domains of p53 N/C terminus at 3-D level. After more than ten years molecular biological researching and testing, a great quantity of the p53 mutation data was accumulated. Selectively utilize these mutation materials, and the data of x-ray diffraction crystal structure of the core domain of p53 protein, we performed a molecular dynamics research on ten different residue substitute models that occurring at three hot spots of Ar175, Arg 249 and Arg 248. The result shows that the core domain of p53 protein keeps its normal conformation during the whole 12ps dynamics progress. This suggested that the core domain of p53 protein not only has a stability of resistant proteolysis but also keeps a higher stability on its molecular mechanics. On the contrast, at the same conditions, most of those residue substitute forms changed their basic 3-D structures after 12ps dynamics progresses. Theirs DNA binding surfaces lost initial functional conformation; some of them even discomposed the sandwich scaffold structure. Due to the residue substitute, the hydrophobic core of p53 protein became exposed, and the whole core domain has a tendency of being distintegrated. The results of this dynamics research directly and substantially enriched the foundations of different characteristics of biochemistry and immunity that exist between wild-type and mutant p53 proteins from 3-D conformation aspect.
语种	中文
学科主题	生物学
公开日期	2016-05-03
页码	87
内容类型	学位论文
源URL	[http://ir.ynao.ac.cn/handle/114a53/4361]
专题	云南天文台_其他
推荐引用方式 GB/T 7714	张彦. P53蛋白质的末端二级结构预测及核心区点突变模拟研究[D]. 昆明. 中国科学院云南天文台. 1999.

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