Comparative Analysis Of Protein 3-dimensional Structure

我们已经开发了比较和比对蛋白质三维结构的算法。Vast(载体比对搜索工具)通过比较SSE(二级结构元素)的类型、连通性和相对取向来确定子结构相似性。通过考虑最佳比对中可重叠的SSE对的数量和分数以及采样的备选比对的数量，客观地识别出惊人的相似之处。还客观地确定了最优的逐个残基的比对，因为具有最令人惊讶的叠加残基和比对残基数量的组合。工作重点放在三个方面。首先是构建一个自动增量更新系统，维护公共数据库中域结构之间的结构邻居关系的全盘数据库。庞大的邻居数据库现在包含超过7000万个构造叠加排列。第二个领域是构建一个“即时”结构邻居服务器，目前结构生物学家正在使用该服务器。该服务器允许他们传输机密坐标数据，用于与公共结构数据库进行大量比较，以识别可能的远程同源，并将特征从一个家庭成员映射到另一个家庭成员。第三个领域的工作是一项研究项目，旨在区分因共同祖先基因的后裔而相关的结构邻居，以及因趋同于能量偏好的折叠基序而相关的结构邻居。我们已经证明，与先前提出的任何措施相比，通过对HCS(同源核心结构)的测试可能更好地区分同系物和“类似物”。HCS(同源核心结构)是先前确定的同源物中保守的亚结构。研究正在进行中，以完全自动化的HCS计算，并构建由HCS重叠聚集的同源蛋白质结构域的多个结构比对。这项研究已经导致了一种新的结构邻域的图形显示系统，该系统允许对影响HCS的区域的保护进行视觉识别。另一个持续进行的项目涉及确定保守的相互作用或对接模式。比较相互作用的结构域对，以确定相互作用的域在结构上是否相似，并测量它们的相对对接方向有多相似。我们打算调查交互模式相似性分数是否可以用于聚类，以识别进化上保守的交互模式。

We have developed algorithms for comparison and alignment of protein three dimensional structures. VAST (vector alignment search tool) identifies substructure similarities by comparing the types, connectivity, and relative orientations of SSE's (secondary structure elements). Surprising similarities are identified objectively, by considering the number and scores of superimposable SSE-pairs in the best alignment, and the number of alternative alignments sampled. An optimal residue-by-residue alignments are also identified objectively, as that with the most surprising combination of superposition residual and number of aligned residues. Work has focused in three areas. The first is construction of an automated incremental update system, to maintain an all-against-all database of the "structure neighbor" relationships among domain structures in the public database. The VAST neighbor database now contains over 70 million structural superpositions alignments. The second area is construction of an "on-the-fly" structure neighbor server, which is now in use by structural biologists. This server allows them to transmit confidential coordinate data for VAST comparison against the public structure database, to identify possible remote homologs and to map features from one family member to another. The third area of work has been a research project aimed at distinguishing structure neighbors that are related by descent from a common ancestral gene from those that are related by convergence to energetically preferred folding motifs. We have shown that homologs and "analogs", as they have been called, may be better distinguished by a test for the HCS (Homologous Core Structure), the substructure conserved among previously identified homologs, than by any measures proposed earlier. Research is in progress to fully automate HCS calculations, and to construct multiple structure alignments of homologous protein domains as clustered by HCS overlap. This research has led to a new graphical display system for structure neighbors, that allows conservation of regions contributing to the HCS to be identified visually. Another continuing project involves identification of conserved interaction or docking modes. Pairs of structural domains that interact with one another are compared, to determine whether the interacting domains are structurally similar, and to measuer how similar are their relative docking orientation. We intend to investigate whether interaction mode similarity scores can be used in clustering, to identify evolutionarily conserved intearaction modes.