automated hierarchical classification of protein domain subfamilies based on functionally-divergent residue signatures自动分层分类基于functionally-divergent残留的蛋白质域亚科签名.pdfVIP

Neuwald et al. BMC Bioinformatics 2012, 13:144 /1471-2105/13/144 METHODOLOGY ARTICLE Open Access Automated hierarchical classification of protein domain subfamilies based on functionally-divergent residue signatures Andrew F Neuwald1*, Christopher J Lanczycki2 and Aron Marchler-Bauer2 Abstract Background: The NCBI Conserved Domain Database (CDD) consists of a collection of multiple sequence alignments of protein domains that are at various stages of being manually curated into evolutionary hierarchies based on conserved and divergent sequence and structural features. These domain models are annotated to provide insights into the relationships between sequence, structure and function via web-based BLAST searches. Results: Here we automate the generation of conserved domain (CD) hierarchies using a combination of heuristic and Markov chain Monte Carlo (MCMC) sampling procedures and starting from a (typically very large) multiple sequence alignment. This procedure relies on statistical criteria to define each hierarchy based on the conserved and divergent sequence patterns associated with protein functional-specialization. At the same time this facilitates the sequence and structural annotation of residues that are functionally important. These statistical criteria also provide a means to objectively assess the quality of CD hierarchies, a non-trivial task considering that the protein subgroups are often very distantly related—a situation in which standard phylogenetic methods can be unreliable. Our aim here is to automatically generate (typically sub-optimal) hierarchies that, based on statistical criteria and visual comparisons, are comparable to manually curated hierarchies; this serves as the first step toward the ultimate goal of obtaining optimal hierarchical classifications. A plot of runtimes for the most time-i