以蛋白質結構字元集研究結構與功能之相關性

Abstract

過去幾年，生物功能與系統網路的相關研究發展逐漸加快。由於結構基因體學技術愈漸成熟，蛋白質資料庫所紀錄之結構數量迅速增加，截至2009年七月為止，已有超過五萬八千個蛋白質結構被結晶。然而在此同時，結晶結構已被解出，但是尚無法立即明瞭其生物性功能的蛋白質也隨之日漸增加。因此，現今非常急需發展有效率之生物資訊方法，以研究新結晶之蛋白質的結構同源性與演化分類。 針對上述議題，前人提出了數個方法，其中心思想是將蛋白質的局部結構片段，根據Ca三度空間座標資訊轉換成一級編碼之結構字元集，藉此研究蛋白質結構相似性與功能分類。為了研究結構與功能之間的關係，我們發展了一系列創新的研究，包括以kappa-alpha 角度為基礎之結構字元集以及類BLOSUM之計分陣列，發現局部結構資訊比胺基酸序列更具有演化上的保留性。 我們將此創新的結構字元集與計分陣列進一步發展為蛋白質快速搜尋比對與功能分類之工具：3D-BLAST及fastSCOP。3D-BLAST以BLAST為搜尋引擎，可以快速尋找同源結構蛋白質，藉以分析新結晶結構，並且具有BLAST之特性，包括可信賴的統計基礎和快速有效之搜尋能力。我們亦提供fastSCOP網頁服務，用以快速辨認結構功能性區域與演化分類。fastSCOP結合了3D-BLAST與結構比對工具，在快速搜尋SCOP資料庫後，再確定結構相似度，並調整功能性區域之範圍，最後輸出演化上分類。 我們的研究結果證實，以kappa-alpha 角度為基礎之結構字元集可代表蛋白質局部片段。而3D-BLAST與fastSCOP在辨識新結晶結構之演化分類與功能推測的應用上，是為有用且可信之工具服務。3D-BLAST和fastSCOP的網址分別為http://3d-blast.life.nctu.edu.tw/及http://fastscop.life.nctu.edu.tw/。

In the past few decades, the knowledge about biological function and systems has grown rapidly. As structural genomics research provides structural models in genome-wide strategies, the number of protein structures in the Protein Data Bank (PDB) is rapidly rising; as of as of 7-July-2009, there were more than 58,000 proteins. Besides, the accumulating known protein structures with unknown or unassigned functions emphasize the demand of effective bioinformatics methods with which to annotate the structural homology or evolutionary family. To address the anterior issues, some approaches have been proposed to encode the 3D local structural fragments based on Ca coordinates into a 1D representation based on several letters, also called as 'structural alphabets'. In order to make a study of current structure–function gap, we developed a series of research, including a novel kappa-alpha plot derived structural alphabet and a novel BLOSUM-like substitution matrix, and explored the structure information based on the fact that the local structure is generally more evolutionary conserved than the amino acid sequence. We have utilized the theory of structural alphabet to rapidly compare protein structure, homologs search (3D-BLAST) and SCOP superfamily assignment (fastSCOP). We present a novel protein structure database search tool, 3D-BLAST, that is useful for analyzing novel structures and can return a ranked list of alignments. This tool has the features of BLAST (for example, robust statistical basis, and effective and reliable search capabilities). In addition, we propose a web server, named fastSCOP, which rapidly identifies the structural domains and determines the evolutionary superfamilies of a query protein structure. fastSCOP server uses 3D-BLAST to scan quickly a large structural classification database and the top ten different superfamilies of protein domains are obtained from the hit lists. And then, a detailed structural alignment tool is adopted to align these top ten structures to refine domain boundaries and to identify evolutionary superfamilies. With the encouraging results shown, kappa-alpha plot derived structural alphabet is adopted to develop represent the backbone fragments and the 3D-BLAST and fastSCOP is robust and can be a useful server for recognizing the evolutionary classifications and the protein functions of novel structures. 3D-BLAST and fastSCOP are available at http://3d-blast.life.nctu.edu.tw/ and http://fastscop.life.nctu.edu.tw/, respectively.