Suboptimal alignments improve the detection of weak homologs in sequence database searches

PSI-BLAST remains one of the popular tools for searching remote homologs in sequence databases. We recently demonstrated that hybrid alignment can function as the alignment core for PSI-BLAST without loss of sensitivity. Here, we start to exploit the benefits of hybrid alignment. We show that incorporating information about the suboptimal alignments, otherwise ignored in PSI-BLAST, already improves the sensitivity of our enhanced version of PSI-BLAST. More interestingly, we find a set of sequences on which our tool disagrees with the classification given by SCOP. Careful examination points to a possible misclassification in SCOP. Cross-referencing with two other methods of protein structure classification, CATH and DALI, supports this view, indicating that the enriched information from suboptimal alignments is valuable for detecting more weakly homologous sequences.