Multiple sequence alignment based on profile alignment of intermediate sequences

Despite considerable efforts, it remains difficult to obtain accurate multiple sequence alignments. By using additional hits from database search of the input sequences, a few strategies have been proposed to significantly improve alignment accuracy, including the construction of profiles from the hits while performing profile alignment, the inclusion of high scoring hits into the input sequences, the use of intermediate sequence search to link distant homologs, and the use of secondary structure information. We develop an algorithm that integrates these strategies to further improve alignment accuracy by modifying the pair-Hidden Markov Model (HMM) approach in ProbCons to incorporate profiles of intermediate sequences from database search and utilize secondary structure predictions as in SPEM. We test our algorithm on a few sets of benchmark multiple alignments, including BAliBASE, HOMSTRAD, PREFAB, and SABmark, and show that it significantly outperforms MAFFT and ProbCons, which are among the best multiple alignment algorithms that do not utilize additional information, and SPEM, which is among the best multiple alignment algorithms that utilize additional hits from database search. The improvement in accuracy over SPEM can be as much as 5-10% when aligning divergent sequences. A software program that implements this approach (ISPAlign) is available at http://faculty.cs.tamu.edu/shsze/ispalign.