Abstract
BackgroundShape complementarity and non-covalent interactions are believed to drive protein-ligand interaction. To date protein-protein, protein-DNA, and protein-RNA interactions were systematically investigated, which is in contrast to interactions with small ligands. We investigate the role of covalent and non-covalent bonds in protein-small ligand interactions using a comprehensive dataset of 2,320 complexes.Methodology and Principal FindingsWe show that protein-ligand interactions are governed by different forces for different ligand types, i.e., protein-organic compound interactions are governed by hydrogen bonds, van der Waals contacts, and covalent bonds; protein-metal ion interactions are dominated by electrostatic force and coordination bonds; protein-anion interactions are established with electrostatic force, hydrogen bonds, and van der Waals contacts; and protein-inorganic cluster interactions are driven by coordination bonds. We extracted several frequently occurring atomic-level patterns concerning these interactions. For instance, 73% of investigated covalent bonds were summarized with just three patterns in which bonds are formed between thiol of Cys and carbon or sulfur atoms of ligands, and nitrogen of Lys and carbon of ligands. Similar patterns were found for the coordination bonds. Hydrogen bonds occur in 67% of protein-organic compound complexes and 66% of them are formed between NH- group of protein residues and oxygen atom of ligands. We quantify relative abundance of specific interaction types and discuss their characteristic features. The extracted protein-organic compound patterns are shown to complement and improve a geometric approach for prediction of binding sites.Conclusions and SignificanceWe show that for a given type (group) of ligands and type of the interaction force, majority of protein-ligand interactions are repetitive and could be summarized with several simple atomic-level patterns. We summarize and analyze 10 frequently occurring interaction patterns that cover 56% of all considered complexes and we show a practical application for the patterns that concerns interactions with organic compounds.
Highlights
Protein-protein and protein-ligand docking are among the central topics in structural biology
We summarize and analyze 10 frequently occurring interaction patterns that cover 56% of all considered complexes and we show a practical application for the patterns that concerns interactions with organic compounds
For the protein-organic compound interactions, we focus on the hydrogen and covalent bonds since they exhibit more regular and frequent patterns than the van der Waals contacts
Summary
Protein-protein and protein-ligand docking are among the central topics in structural biology. A recent study by Thornton’s group reveals that pockets binding the same ligand show greater variation in their shapes than can be accounted for by the conformational variability of the ligand, which suggests that the geometrical complementarity is not sufficient to drive molecular recognition process [17] This prompts our investigation into the interactions between proteins and ligands, in which we analyze both covalent bonds (normal covalent bonds and coordination bonds) and non-covalent bonds (electrostatic force, hydrogen bonds and van der Waals force). We show, using a case study that concerns recent blind (without the knowledge of the ligand) geometric method for prediction of the binding sites, that usage of several patters in tandem improves the binding site predictions and that the sites predicted using patterns are complementary to the results based on the geometric analysis of the protein surface Discovery of such interaction patterns would provide a comprehensive overview of protein-ligand interactions, but it would facilitate design of binding site prediction methods and high-throughput molecular docking procedures. We investigate the role of covalent and non-covalent bonds in protein-small ligand interactions using a comprehensive dataset of 2,320 complexes
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