Motivation: Sequence similarity searches performed with BLAST, SSEARCH and FASTA achieve high sensitivity by using scoring matrices (e. g. BLOSUM62) that target low identity (<33%) alignments. Although such scoring matrices can effectively identify distant homologs, they can also produce local alignments that extend beyond the homologous regions. Results: We measured local alignment start/stop boundary accuracy using a set of queries where the correct alignment boundaries were known, and found that 7% of BLASTP and 8% of SSEARCH alignment boundaries were overextended. Overextended alignments include non-homologous sequences; they occur most frequently between sequences that are more closely related (> 33% identity). Adjusting the scoring matrix to reflect the identity of the homologous sequence can correct higher identity overextended alignment boundaries. In addition, the scoring matrix that produced a correct alignment could be reliably predicted based on the sequence identity seen in the original BLOSUM62 alignment. Realigning with the predicted scoring matrix corrected 37% of all overextended alignments, resulting in more correct alignments than using BLOSUM62 alone.
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