Several efforts have been made since 1990 to overcome the effort required to maintain curated protein family data- bases by automatically clustering the protein sequence databases using sequence similarity. The general approach is to compute all possible pairwise comparisons, and then cluster them in some fashion, shifting the effort from humans to computers. This otherwise computationally very demanding process has benefited from the introduc- tion of the rapid PSI-BLAST system(Altschul et al., 1997). PSI-BLAST starts searching with a single sequence but then makes a multiple alignment PSSMfrom the hits after one iteration, then searches with it, and so forth. Problems with any clustering method include deciding how to delineate clusters (usually on the.
