Homology-extended sequence alignment

This paper introduces the novel method of contact-based protein sequence alignment, where structural information in the form of contact mutation prob-abilities is incorporated into an alignment routine using contact-mutation matrices (CAO: Contact Accepted mutatiOn). The contact-based alignment routine optimizes the score of matched contacts, which involves four (two per contact) instead of two residues per match in pairwise alignments. The ®rst contact refers to a real side-chain contact in a template sequence with known structure, and the second contact is the equivalent putative contact of a homologous query sequence with unknown structure. An algorithm has been devised to perform a pairwise sequence alignment based on contact information. The contact scores were combined with PAM-type (Point Accepted Mutation) substitu-tion scores after parameterization of gap penalties and score weights by means of a genetic algorithm. We show that owing to the structural information contained in the CAO matrices, signi®cantly improved alignments of distantly related sequences can be obtained. This has allowed us to annotate eight putative Drosophila IGF sequences. Contact-based sequence alignment should therefore prove useful in comparative modelling and fold recognition