title: Fold homology detection using sequence fragment composition profiles of proteins.
abstract: The effectiveness of sequence alignment in detecting structural homology among protein sequences decreases markedly when pairwise sequence identity is low (the so-called "twilight zone" problem of sequence alignment). Alternative sequence comparison strategies able to detect structural kinship among highly divergent sequences are necessary to address this need. Among them are alignment-free methods, which use global sequence properties (such as amino acid composition) to identify structural homology in a rapid and straightforward way. We explore the viability of using tetramer sequence fragment composition profiles in finding structural relationships that lie undetected by traditional alignment. We establish a strategy to recast any given protein sequence into a tetramer sequence fragment composition profile, using a series of amino acid clustering steps that have been optimized for mutual information. Our method has the effect of compressing the set of 160,000 unique tetramers (if using the 20-letter amino acid alphabet) into a more tractable number of reduced tetramers (approximately 15-30), so that a meaningful tetramer composition profile can be constructed. We test remote homology detection at the topology and fold superfamily levels using a comprehensive set of fold homologs, culled from the CATH database that share low pairwise sequence similarity. Using the receiver-operating characteristic measure, we demonstrate potentially significant improvement in using information-optimized reduced tetramer composition, over methods relying only on the raw amino acid composition or on traditional sequence alignment, in homology detection at or below the "twilight zone".
authors.affiliation: Department of Biological Sciences, New York City College of Technology, The City University of New York, Brooklyn, New York 11201, USA. asolis@citytech.cuny.edu
authors.forename: Armando D
authors.initials: AD
authors.lastname: Solis
authors.forename: Shalom R
authors.initials: SR
authors.lastname: Rackovsky
mesh_terms: D000465:Algorithms; D016000:Cluster Analysis; D016208:Databases, Factual; D017510:Protein Folding; D055503:Protein Multimerization; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D016415:Sequence Alignment / Q000379:methods; D017386:Sequence Homology, Amino Acid
chemical_list: D011506:Proteins