标题: | 蛋白质结构、结构聚集和序列保留性之间的关系 On the relationship between protein structures, packing density, and residue conservation of protein domains |
作者: | 林玉凤 黄镇刚 Lin, Yu-Feng Hwang, Jenn-Kang 生物资讯及系统生物研究所 |
关键字: | 加权接触数;序列保留性;金属离子结合位;片段转置矩阵方法;weighted contact number;sequence conservation;fragment transformation method;metal ion binding sites prediction;MIB |
公开日期: | 2017 |
摘要: | 蛋白质通常依照胺基酸序列折叠成独特、稳定而有序的结构,使得所得到的蛋白质可以执行其特定的功能。因此,对于执行功能和维持结构稳定性重要的氨基酸在序列和结构方面通常是高度保留的。近来有研究探讨了序列的保留性赋予蛋白质在结构上的限制,并且发现氨基酸序列保留度(sequence conservation)与溶剂可接触性(solvent accessibility)以及与根据胺基酸主链C原子计算加权接触数(weighted contact number)所得的局部结构聚集密度(local packing density)间的高度相关性。源自序列比对的位点特异性取代率计算而来的序列保留度和由三维结构得到的局部结构聚集密度之间的关系表明,蛋白质序列和结构的演化约束是相互关联的。在本论文中,我们首先从相似的蛋白质结构中计算结构聚集密度曲线之间的关系,由SCOP资料库所定义的有着远端同源(remote homolog)关系的超家族蛋白质结构域(Superfamily domains)间,相似的结构具有相似的加权接触数分布,这显示局部结构聚集密度分布可以反映出蛋白质的结构限制。接着,样本资料集中两个蛋白质的位点特异性替代率谱(site-specific substitution rate profiles)与彼此的结构,结果亦显示,相似的序列保留度可能与相似的结构相关。蛋白质序列和结构的进化约束不仅在同一个蛋白质中相互关联,而且可能在不同的蛋白质中也有着相互关联的现象。 另一方面,受演化限制的蛋白质序列和结构导致功能结合区域在序列和结构中趋向保留,而且涉及交互作用的氨基酸通常处于邻近的三维空间中。在本论文中,我们除了分析以上蛋白质整体结构层级,接着探讨局部结构的影响。以金属离子结合位的蛋白质结构为例,我们分析了金属离子结合位的蛋白质结构,局部聚集密度分布和氨基酸构成,包含了钙离子( Ca2+), 铜离子( Cu2+), 亚铜离子( Cu+), 铁离子(Fe3+), 亚铁离子(Fe2+), 镁离子(Mg2+), 锰离子(Mn2+), 锌离子(Zn2+), 镉离子(Cd2+), 镍离子(Ni2+), 汞离子(Hg2+)和钴离子(Co2+)。金属离子结合位的局部聚集密度分析显示,金属离子结合位在蛋白质中往往位于较拥挤的环境。我们的结果表明,金属离子结合氨基酸的局部聚集密度分布与非金属离子结合氨基酸的分布是明显不同的。这12种金属离子结合位具有明显不同的结合模式,显示出金属离子结合氨基酸中结构和序列的保留性。根据保留度高的立体结构和氨基酸模式,我们进一步开发了一种通过利用片段变换方法(fragment transformation method)预测金属离子结合氨基酸和建立金属离子对接模型,并且构建了MIB伺服器(Metal Ion Binding sites prediction and docking server, http://bioinfo.cmu.edu.tw/MIB/)不仅有十二个金属离子结合位的预测,而且提供金属离子对接(metal ions docking)的模型。 During evolution, substitutions at individual residues within amino acid sequences arise under the constraints of structure folding, protein function, and the protein–protein interactions. Amino acid sequences generally fold into unique, stable, and well-ordered conformations so that the resulting proteins can carry out their specific functions. As such, residues that are important for function and structural stabilization are generally highly conserved in terms of both sequence and structure. Recent studies have discussed the structural constraints imparted by site-specific substitutions, and amino acid sequence conservation was found to correlate with solvent accessibility and the local packing density such as weighted contact number. The relationship between sequence conservation, site-specific substitution rates derived from multiple sequence alignment, and the weighted contact number, local packing density derived from three-dimensional structure, revealed that the evolution constraint of protein sequence and structure properties were correlated. In this study, we assessed the relationship between the packing density profiles drawn out from similar protein domain structures in SCOP superfamily with the relationship of remote homologs, and the results showed that similar structures had similar weighted contact number profiles, and demonstrated that the packing density profiles could reflect the structural constraints. Then, we compared the site-specific substitution rate profiles of two proteins and their structures, and the results showed that similar conservation profiles could be linked to similar structures. The evolution constraints of protein sequence and structure were not only related to each other in a protein, but also were interrelated in different proteins. The protein sequence and structure restricted by evolution constraints lead to that the binding regions tend to be conserved in sequence and structure and the interacting residues involved are usually in close three-dimensional space. In this study, we analyzed the protein structure, local packing density and residue constitute of metal ion-binding sites, including Ca2+, Cu2+, Cu+, Fe3+, Fe2+, Mg2+, Mn2+, Zn2+, Cd2+, Ni2+, Hg2+, and Co2+. The analysis of local packing density of metal ion-binding sites revealed that the metal ion-binding sites tend to be more crowded in proteins. Our result showed that the distributions of local packing density of metal ion-binding residues were distinct from those of non-metal ion-binding residues. The results showed that there were distinct different binding patterns of these twelve kinds of metal ion-binding sites, indicating the conservation of structure and sequence in metal ion-binding residues. According to the conserved patterns of structure and residue, we further developed a method to predict the metal ion-binding residues and build the model of metal ions docking by using fragment transformation method, and built up the MIB server (Metal Ion Binding sites prediction and docking server, http://bioinfo.cmu.edu.tw/MIB/) for not only twelve metal ion–binding sites prediction but also metal ions docking. |
URI: | http://etd.lib.nctu.edu.tw/cdrfb3/record/nctu/#GT079951810 http://hdl.handle.net/11536/141877 |
显示于类别: | Thesis |