Journal
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Volume 80, Issue 1, Pages 126-141Publisher
WILEY
DOI: 10.1002/prot.23169
Keywords
protein-protein interaction; protein interaction site prediction; phylogenetic substitution model; mutation pattern; sequence analysis
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Funding
- National Institute of General Medical Sciences of the National Institutes of Health [R01 GM075004]
- National Science Foundation [DMS800568, IIS0915801, EF0850009]
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Proteinprotein binding events mediate many critical biological functions in the cell. Typically, functionally important sites in proteins can be well identified by considering sequence conservation. However, proteinprotein interaction sites exhibit higher sequence variation than other functional regions, such as catalytic sites of enzymes. Consequently, the mutational behavior leading to weak sequence conservation poses significant challenges to the proteinprotein interaction site prediction. Here, we present a phylogenetic framework to capture critical sequence variations that favor the selection of residues essential for proteinprotein binding. Through the comprehensive analysis of diverse protein families, we show that protein binding interfaces exhibit distinct amino acid substitution as compared with other surface residues. On the basis of this analysis, we have developed a novel method, BindML, which utilizes the substitution models to predict proteinprotein binding sites of protein with unknown interacting partners. BindML estimates the likelihood that a phylogenetic tree of a local surface region in a query protein structure follows the substitution patterns of protein binding interface and nonbinding surfaces. BindML is shown to perform well compared to alternative methods for protein binding interface prediction. The methodology developed in this study is very versatile in the sense that it can be generally applied for predicting other types of functional sites, such as DNA, RNA, and membrane binding sites in proteins. Proteins 2012. (C) 2011 Wiley Periodicals, Inc.
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