title: Sequence comparison by sequence harmony identifies subtype-specific functional sites.
abstract: Multiple sequence alignments are often used to reveal functionally important residues within a protein family. They can be particularly useful for the identification of key residues that determine functional differences between protein subfamilies. We present a new entropy-based method, Sequence Harmony (SH) that accurately detects subfamily-specific positions from a multiple sequence alignment. The SH algorithm implements a novel formula, able to score compositional differences between subfamilies, without imposing conservation, in a simple manner on an intuitive scale. We compare our method with the most important published methods, i.e. AMAS, TreeDet and SDP-pred, using three well-studied protein families: the receptor-binding domain (MH2) of the Smad family of transcription factors, the Ras-superfamily of small GTPases and the MIP-family of integral membrane transporters. We demonstrate that SH accurately selects known functional sites with higher coverage than the other methods for these test-cases. This shows that compositional differences between protein subfamilies provide sufficient basis for identification of functional sites. In addition, SH selects a number of sites of unknown function that could be interesting candidates for further experimental investigation.
authors.affiliation: Centre for Integrative Bioinformatics VU (IBIVU), Vrije Universiteit, De Boelelaan 1081A, 1081 HV Amsterdam, The Netherlands.
authors.forename: Walter
authors.initials: W
authors.lastname: Pirovano
authors.forename: K Anton
authors.initials: KA
authors.lastname: Feenstra
authors.forename: Jaap
authors.initials: J
authors.lastname: Heringa
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D019277:Entropy; D026901:Membrane Transport Proteins / Q000737:chemistry; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein; D051785:Smad Proteins / Q000737:chemistry; D018631:ras Proteins / Q000737:chemistry
chemical_list: D026901:Membrane Transport Proteins; D051785:Smad Proteins; D018631:ras Proteins