We have developed MUMMALS, a program to construct multiple protein sequence alignment using probabilistic consistency. MUMMALS improves alignment quality by using pairwise alignment hidden Markov models (HMMs) with multiple match states that describe local structural information without exploiting explicit structure predictions. Parameters for such models have been estimated from a large library of structure-based alignments. We show that (i) on remote homologs, MUMMALS achieves statistically best accuracy among several leading aligners, such as ProbCons, MAFFT and MUSCLE, albeit the average improvement is small, in the order of several percent; (ii) a large collection (>10 000) of automatically computed pairwise structure alignments of divergent protein domains is superior to smaller but carefully curated datasets for estimation of alignment parameters and performance tests; (iii) reference-independent evaluation of alignment quality using sequence alignment-dependent structure superpositions correlates well with reference-dependent evaluation that compares sequence-based alignments to structure-based reference alignments.
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