Protein sequence alignment with family-specific amino acid similarity matrices

Abstract

Abstract Background Alignment of amino acid sequences by means of dynamic programming is a cornerstone sequence comparison method. The quality of alignments produced by dynamic programming critically depends on the choice of the alignment scoring function. Therefore, for a specific alignment problem one needs a way of selecting the best performing scoring function. This work is focused on the issue of finding optimized protein family- and fold-specific scoring functions for global similarity matrix-based sequence alignment. Findings I utilize a comprehensive set of reference alignments obtained from structural superposition of homologous and analogous proteins to design a quantitative statistical framework for evaluating the performance of alignment scoring functions in global pairwise sequence alignment. This framework is applied to study how existing general-purpose amino acid similarity matrices perform on individual protein families and structural folds, and to compare them to family-specific and fold-specific matrices derived in this work. I describe an adaptive alignment procedure that automatically selects an appropriate similarity matrix and optimized gap penalties based on the properties of the sequences being aligned. Conclusions The results of this work indicate that using family-specific similarity matrices significantly improves the quality of the alignment of homologous sequences over the traditional sequence alignment based on a single general-purpose similarity matrix. However, using fold-specific similarity matrices can only marginally improve sequence alignment of proteins that share the same structural fold but do not share a common evolutionary origin. The family-specific matrices derived in this work and the optimized gap penalties are available at http://taurus.crc.albany.edu/fsm.