Global Alignment of Protein Sequences with Position-Specific Scoring Matrices.

NCBI目前使用本地比对工具“rp - blast”来搜索CDD。局部对齐工具本质上不适合CDD检索，因为完整域（根据定义）是进化中保守的单元。因此，检索应该将完整结构域与蛋白质子序列进行比较，这是“半全局”比对。因此，我们开发了一种半全局比对算法和一种新的统计近似方法，可以在查询的蛋白质序列中发现整个蛋白质结构域，从而为新蛋白质序列的功能提供线索。Sergey Sheetlin博士在一个名为“GLOBAL”的程序中将我们的方法作为动态规划算法实现。Kann博士分析了几种竞争方法的检索效率，包括hmm，一种隐马尔可夫模型（hmm）的实现，并显示了检索效率的顺序：HMMer（在全局模式下）与global差不多，比rpps - blast好。GLOBAL实际上是一个简并HMM。在保留HMM检索效率的同时，GLOBAL足够简单，可以使用与BLAST等局部对齐方法相同的启发式方法来加速。最近，Carroll博士已经完成了使用半全局比对的迭代蛋白质搜索工具的第一阶段开发，并将结果代码纳入NCBI CoreTools。GLOBAL代码的启发式加速将其速度提高了大约一个数量级，使其速度与其他领域检索工具具有竞争力。

NCBI currently uses the local alignment tool "rps-BLAST" to search the CDD. Local alignment tools are inherently inappropriate for CDD retrieval, because complete domains (by definition) are the units conserved in evolution. Thus, retrieval should compare complete domains to protein subsequences, which is "semi-global" alignment. Accordingly, we developed a semi-global alignment algorithm and a novel statistical approximation that discovers whole protein domains within a query protein sequence, thereby giving clues as to the function of novel protein sequences. Dr Sergey Sheetlin implemented our method as a dynamic-programming algorithm in a program called "GLOBAL". Dr Kann analyzed the retrieval efficacy of several competitive methods, including HMMer, an implementation of Hidden Markov models (HMMs), and shown that the retrieval efficacies are in the order: HMMer (in global mode) about the same as GLOBAL better than rps-BLAST. GLOBAL is in fact a degenerate HMM. While retaining HMM retrieval efficacies, GLOBAL is simple enough to be accelerated by the same heuristics used in local alignment methods like BLAST. Recently, Dr. Carroll has completed the first stage of development of an iterative protein search tool using semi-global alignment and has incorporated the resulting code in the NCBI CoreTools. The heuristic acceleration of the GLOBAL code speeds it by about an order of magnitude, making its speed competitive with other domain-retrieval tools.