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A comprehensive survey of small-molecule binding pockets in proteins.

ABSTRACT: Many biological activities originate from interactions between small-molecule ligands and their protein targets. A detailed structural and physico-chemical characterization of these interactions could significantly deepen our understanding of protein function and facilitate drug design. Here, we present a large-scale study on a non-redundant set of about 20,000 known ligand-binding sites, or pockets, of proteins. We find that the structural space of protein pockets is crowded, likely complete, and may be represented by about 1,000 pocket shapes. Correspondingly, the growth rate of novel pockets deposited in the Protein Data Bank has been decreasing steadily over the recent years. Moreover, many protein pockets are promiscuous and interact with ligands of diverse scaffolds. Conversely, many ligands are promiscuous and interact with structurally different pockets. Through a physico-chemical and structural analysis, we provide insights into understanding both pocket promiscuity and ligand promiscuity. Finally, we discuss the implications of our study for the prediction of protein-ligand interactions based on pocket comparison.

SUBMITTER: Gao M

PROVIDER: S-EPMC3812058 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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A comprehensive survey of small-molecule binding pockets in proteins.

Gao Mu M Skolnick Jeffrey J

PLoS computational biology 20131024 10

Many biological activities originate from interactions between small-molecule ligands and their protein targets. A detailed structural and physico-chemical characterization of these interactions could significantly deepen our understanding of protein function and facilitate drug design. Here, we present a large-scale study on a non-redundant set of about 20,000 known ligand-binding sites, or pockets, of proteins. We find that the structural space of protein pockets is crowded, likely complete, a ...[more]

PMID: 24204237

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Project description:BackgroundThe study of protein-small molecule interactions is vital for understanding protein function and for practical applications in drug discovery. To benefit from the rapidly increasing structural data, it is essential to improve the tools that enable large scale binding site prediction with greater emphasis on their biological validity.ResultsWe have developed a new method for the annotation of protein-small molecule binding sites, using inference by homology, which allows us to extend annotation onto protein sequences without experimental data available. To ensure biological relevance of binding sites, our method clusters similar binding sites found in homologous protein structures based on their sequence and structure conservation. Binding sites which appear evolutionarily conserved among non-redundant sets of homologous proteins are given higher priority. After binding sites are clustered, position specific score matrices (PSSMs) are constructed from the corresponding binding site alignments. Together with other measures, the PSSMs are subsequently used to rank binding sites to assess how well they match the query and to better gauge their biological relevance. The method also facilitates a succinct and informative representation of observed and inferred binding sites from homologs with known three-dimensional structures, thereby providing the means to analyze conservation and diversity of binding modes. Furthermore, the chemical properties of small molecules bound to the inferred binding sites can be used as a starting point in small molecule virtual screening. The method was validated by comparison to other binding site prediction methods and to a collection of manually curated binding site annotations. We show that our method achieves a sensitivity of 72% at predicting biologically relevant binding sites and can accurately discriminate those sites that bind biological small molecules from non-biological ones.ConclusionsA new algorithm has been developed to predict binding sites with high accuracy in terms of their biological validity. It also provides a common platform for function prediction, knowledge-based docking and for small molecule virtual screening. The method can be applied even for a query sequence without structure. The method is available at http://www.ncbi.nlm.nih.gov/Structure/ibis/ibis.cgi.

Dataset Information

A comprehensive survey of small-molecule binding pockets in proteins.

Publications

A comprehensive survey of small-molecule binding pockets in proteins.

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