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Protein functional surfaces: global shape matching and local spatial alignments of ligand binding sites.

Binkowski TA, Joachimiak A - BMC Struct. Biol. (2008)

Bottom Line: Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity.Results using surface similarity to predict function for proteins of unknown function are reported.Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA. abinkowski@anl.gov

ABSTRACT

Background: Protein surfaces comprise only a fraction of the total residues but are the most conserved functional features of proteins. Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity. While biochemical activity can be attributed to a few key residues, the broader surrounding environment plays an equally important role.

Results: We describe a methodology that attempts to optimize two components, global shape and local physicochemical texture, for evaluating the similarity between a pair of surfaces. Surface shape similarity is assessed using a three-dimensional object recognition algorithm and physicochemical texture similarity is assessed through a spatial alignment of conserved residues between the surfaces. The comparisons are used in tandem to efficiently search the Global Protein Surface Survey (GPSS), a library of annotated surfaces derived from structures in the PDB, for studying evolutionary relationships and uncovering novel similarities between proteins.

Conclusion: We provide an assessment of our method using library retrieval experiments for identifying functionally homologous surfaces binding different ligands, functionally diverse surfaces binding the same ligand, and binding surfaces of ubiquitous and conformationally flexible ligands. Results using surface similarity to predict function for proteins of unknown function are reported. Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.

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Identification of a threshold for SurfaceShapeSignatures. SSS distances obtained by querying the ATP binding site of cAMP-dependent kinase (PDB:1atp) against the GPSS ligand surface library are plotted against the molecular weight of the ligand corresponding to the library surface (a). Ligands with MW ± 100 D of ATP are highlighted in yellow. The molecular shape similarity Taniomoto score between ATP and the ligand corresponding to the library surface is plotted in (b). Tanimoto scores greater than 0.7 (blue) are generally regarded as similar. The correlation coefficients for molecular weight and shape similarity are 0.46 and 0.45, respectively, and the corresponding regression lines are shown in red. Our selected threshold distance of 0.3 (green) for use in our SurfaceScreen methodology eliminates less than 1% of true-positive surfaces in our benchmarking exercises.
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Figure 2: Identification of a threshold for SurfaceShapeSignatures. SSS distances obtained by querying the ATP binding site of cAMP-dependent kinase (PDB:1atp) against the GPSS ligand surface library are plotted against the molecular weight of the ligand corresponding to the library surface (a). Ligands with MW ± 100 D of ATP are highlighted in yellow. The molecular shape similarity Taniomoto score between ATP and the ligand corresponding to the library surface is plotted in (b). Tanimoto scores greater than 0.7 (blue) are generally regarded as similar. The correlation coefficients for molecular weight and shape similarity are 0.46 and 0.45, respectively, and the corresponding regression lines are shown in red. Our selected threshold distance of 0.3 (green) for use in our SurfaceScreen methodology eliminates less than 1% of true-positive surfaces in our benchmarking exercises.

Mentions: The choice of a shape similarity threshold has a significant impact on the efficiency and specificity of surface library searching. Operating under the pretense that ligands with similar shape and molecular weight are more likely to bind to similar pockets, we correlated these properties to SSS KS distances. Our training data is taken from querying cAMP-dependent kinase (PDB:1atp) ATP binding surface against the GPSS library. With a correlation coefficient of 0.458, we see that some degree of surface similarity can be inferred simply by molecular weight (Figure 2a). We highlight a region on the plot (yellow) that corresponds to +/- 100 D from the molecular weight of ATP and identify the similarity distance of 0.22, along the x-axis, in which only 11% of surfaces exist as outliers. Next, ATP was compared to ligands corresponding to the surfaces in our library using the molecular shape matching application ROCS (OpenEye Scientific Software, Inc). ROCS identifies the best superposition of two molecules by optimizing their overlapping volume and reports a normalized Tanimoto score. Tanimoto values greater than 0.7 are generally regarded as having similar shape and are highlighted on our plot (cyan). The Tanimoto scores are correlated to the SSS distance in Figure 2b. We identify a distance of 0.24, in which only 10% are outliers. Since our assumptions about molecular weight and ligand shape similarity are simplistic and surface comparison hope to identify more evolutionary distant relationships, we set our default threshold distance at 0.3. In the benchmarking retrieval experiments presented in Results section, our default threshold excludes less than 1% of true-positive surfaces, all of which can be justified by unique structural incident (e.g. multiple binding pockets, mutation experiments, low resolution structure, crystallographic error).


Protein functional surfaces: global shape matching and local spatial alignments of ligand binding sites.

Binkowski TA, Joachimiak A - BMC Struct. Biol. (2008)

Identification of a threshold for SurfaceShapeSignatures. SSS distances obtained by querying the ATP binding site of cAMP-dependent kinase (PDB:1atp) against the GPSS ligand surface library are plotted against the molecular weight of the ligand corresponding to the library surface (a). Ligands with MW ± 100 D of ATP are highlighted in yellow. The molecular shape similarity Taniomoto score between ATP and the ligand corresponding to the library surface is plotted in (b). Tanimoto scores greater than 0.7 (blue) are generally regarded as similar. The correlation coefficients for molecular weight and shape similarity are 0.46 and 0.45, respectively, and the corresponding regression lines are shown in red. Our selected threshold distance of 0.3 (green) for use in our SurfaceScreen methodology eliminates less than 1% of true-positive surfaces in our benchmarking exercises.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2626596&req=5

Figure 2: Identification of a threshold for SurfaceShapeSignatures. SSS distances obtained by querying the ATP binding site of cAMP-dependent kinase (PDB:1atp) against the GPSS ligand surface library are plotted against the molecular weight of the ligand corresponding to the library surface (a). Ligands with MW ± 100 D of ATP are highlighted in yellow. The molecular shape similarity Taniomoto score between ATP and the ligand corresponding to the library surface is plotted in (b). Tanimoto scores greater than 0.7 (blue) are generally regarded as similar. The correlation coefficients for molecular weight and shape similarity are 0.46 and 0.45, respectively, and the corresponding regression lines are shown in red. Our selected threshold distance of 0.3 (green) for use in our SurfaceScreen methodology eliminates less than 1% of true-positive surfaces in our benchmarking exercises.
Mentions: The choice of a shape similarity threshold has a significant impact on the efficiency and specificity of surface library searching. Operating under the pretense that ligands with similar shape and molecular weight are more likely to bind to similar pockets, we correlated these properties to SSS KS distances. Our training data is taken from querying cAMP-dependent kinase (PDB:1atp) ATP binding surface against the GPSS library. With a correlation coefficient of 0.458, we see that some degree of surface similarity can be inferred simply by molecular weight (Figure 2a). We highlight a region on the plot (yellow) that corresponds to +/- 100 D from the molecular weight of ATP and identify the similarity distance of 0.22, along the x-axis, in which only 11% of surfaces exist as outliers. Next, ATP was compared to ligands corresponding to the surfaces in our library using the molecular shape matching application ROCS (OpenEye Scientific Software, Inc). ROCS identifies the best superposition of two molecules by optimizing their overlapping volume and reports a normalized Tanimoto score. Tanimoto values greater than 0.7 are generally regarded as having similar shape and are highlighted on our plot (cyan). The Tanimoto scores are correlated to the SSS distance in Figure 2b. We identify a distance of 0.24, in which only 10% are outliers. Since our assumptions about molecular weight and ligand shape similarity are simplistic and surface comparison hope to identify more evolutionary distant relationships, we set our default threshold distance at 0.3. In the benchmarking retrieval experiments presented in Results section, our default threshold excludes less than 1% of true-positive surfaces, all of which can be justified by unique structural incident (e.g. multiple binding pockets, mutation experiments, low resolution structure, crystallographic error).

Bottom Line: Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity.Results using surface similarity to predict function for proteins of unknown function are reported.Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA. abinkowski@anl.gov

ABSTRACT

Background: Protein surfaces comprise only a fraction of the total residues but are the most conserved functional features of proteins. Surfaces performing identical functions are found in proteins absent of any sequence or fold similarity. While biochemical activity can be attributed to a few key residues, the broader surrounding environment plays an equally important role.

Results: We describe a methodology that attempts to optimize two components, global shape and local physicochemical texture, for evaluating the similarity between a pair of surfaces. Surface shape similarity is assessed using a three-dimensional object recognition algorithm and physicochemical texture similarity is assessed through a spatial alignment of conserved residues between the surfaces. The comparisons are used in tandem to efficiently search the Global Protein Surface Survey (GPSS), a library of annotated surfaces derived from structures in the PDB, for studying evolutionary relationships and uncovering novel similarities between proteins.

Conclusion: We provide an assessment of our method using library retrieval experiments for identifying functionally homologous surfaces binding different ligands, functionally diverse surfaces binding the same ligand, and binding surfaces of ubiquitous and conformationally flexible ligands. Results using surface similarity to predict function for proteins of unknown function are reported. Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.

Show MeSH
Related in: MedlinePlus