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Investigation of atomic level patterns in protein--small ligand interactions.

Chen K, Kurgan L - PLoS ONE (2009)

Bottom Line: Similar patterns were found for the coordination bonds.We 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Background: Shape 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 findings: We 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 significance: We 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.

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The structure of Anguilla anguilla agglutinin protein (PDB entry 1K12).The binding sites predicted by Ligsite CSC are colored in green and the binding sites predicted by the pattern-based method are colored in blue. The protein surface is rendered in gray and the ligand is in the stick form. The LigsiteCSC predictions are over 10Å away from any atom of the ligand, while one of pattern-based predictions is 0.67Å away from one of the ligand's atoms. Only 4 predictions by Ligsite CSC and by the pattern-based method are visible; the remaining predictions are on the other side of the protein.
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pone-0004473-g010: The structure of Anguilla anguilla agglutinin protein (PDB entry 1K12).The binding sites predicted by Ligsite CSC are colored in green and the binding sites predicted by the pattern-based method are colored in blue. The protein surface is rendered in gray and the ligand is in the stick form. The LigsiteCSC predictions are over 10Å away from any atom of the ligand, while one of pattern-based predictions is 0.67Å away from one of the ligand's atoms. Only 4 predictions by Ligsite CSC and by the pattern-based method are visible; the remaining predictions are on the other side of the protein.

Mentions: We observe that the prediction from the pattern-based method are complementary to the prediction from Ligsite CSC, i.e., for some proteins the binding sites predicted by Ligsite CSC are relatively far away from the actual binding sites while our method provides correct predictions. For example, for the Anguilla anguilla agglutinin protein (PDB entry 1K12), the 5 prediction generated by Ligsite CSC are at least 11 Å away from the ligand, while one of our predictions is only 0.67Å from the compound, see Figure 10. This motivated a hybrid approach in which predictions from the two methods are combined by taking the top two predictions from LigsiteCSC and the top three pattern-based predictions (on average the third best pattern-based prediction is better than third best prediction from LigsiteCSC). Figure 9 shows that the results based on the merged predictions are better than the results from individual methods, especially for low values of D. For instance, in the case of D = 1, both Ligsite CSC and pattern-based methods predict the binding sites that are within 1Å from the ligand for about 35% of the proteins, while the merged predictions are successful at 46% level. This result indicates that interaction patterns could be utilized to improve existing blind geometrical predictions of binding sites.


Investigation of atomic level patterns in protein--small ligand interactions.

Chen K, Kurgan L - PLoS ONE (2009)

The structure of Anguilla anguilla agglutinin protein (PDB entry 1K12).The binding sites predicted by Ligsite CSC are colored in green and the binding sites predicted by the pattern-based method are colored in blue. The protein surface is rendered in gray and the ligand is in the stick form. The LigsiteCSC predictions are over 10Å away from any atom of the ligand, while one of pattern-based predictions is 0.67Å away from one of the ligand's atoms. Only 4 predictions by Ligsite CSC and by the pattern-based method are visible; the remaining predictions are on the other side of the protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2637420&req=5

pone-0004473-g010: The structure of Anguilla anguilla agglutinin protein (PDB entry 1K12).The binding sites predicted by Ligsite CSC are colored in green and the binding sites predicted by the pattern-based method are colored in blue. The protein surface is rendered in gray and the ligand is in the stick form. The LigsiteCSC predictions are over 10Å away from any atom of the ligand, while one of pattern-based predictions is 0.67Å away from one of the ligand's atoms. Only 4 predictions by Ligsite CSC and by the pattern-based method are visible; the remaining predictions are on the other side of the protein.
Mentions: We observe that the prediction from the pattern-based method are complementary to the prediction from Ligsite CSC, i.e., for some proteins the binding sites predicted by Ligsite CSC are relatively far away from the actual binding sites while our method provides correct predictions. For example, for the Anguilla anguilla agglutinin protein (PDB entry 1K12), the 5 prediction generated by Ligsite CSC are at least 11 Å away from the ligand, while one of our predictions is only 0.67Å from the compound, see Figure 10. This motivated a hybrid approach in which predictions from the two methods are combined by taking the top two predictions from LigsiteCSC and the top three pattern-based predictions (on average the third best pattern-based prediction is better than third best prediction from LigsiteCSC). Figure 9 shows that the results based on the merged predictions are better than the results from individual methods, especially for low values of D. For instance, in the case of D = 1, both Ligsite CSC and pattern-based methods predict the binding sites that are within 1Å from the ligand for about 35% of the proteins, while the merged predictions are successful at 46% level. This result indicates that interaction patterns could be utilized to improve existing blind geometrical predictions of binding sites.

Bottom Line: Similar patterns were found for the coordination bonds.We 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Background: Shape 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 findings: We 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 significance: We 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.

Show MeSH