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Structural deformation upon protein-protein interaction: a structural alphabet approach.

Martin J, Regad L, Lecornet H, Camproux AC - BMC Struct. Biol. (2008)

Bottom Line: Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%).This proportion is even greater in the interface regions (41%).These results could be of help for flexible docking.

View Article: PubMed Central - HTML - PubMed

Affiliation: Equipe de Bioinformatique Génomique et Moléculaire, INSERM UMRS726/Université Denis Diderot Paris 7, F-75005 Paris, France. juliette.martin@jouy.inra.fr

ABSTRACT

Background: In a number of protein-protein complexes, the 3D structures of bound and unbound partners significantly differ, supporting the induced fit hypothesis for protein-protein binding.

Results: In this study, we explore the induced fit modifications on a set of 124 proteins available in both bound and unbound forms, in terms of local structure. The local structure is described thanks to a structural alphabet of 27 structural letters that allows a detailed description of the backbone. Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%). This proportion is even greater in the interface regions (41%). Interface regions preferentially involve coils. Our analysis further reveals that some structural letters in coil are not favored in the interface. We show that certain structural letters in coil are particularly subject to modifications at the interface, and that the severity of structural change also varies. These information are used to derive a structural letter substitution matrix that summarizes the local structural changes observed in our data set. We also illustrate the usefulness of our approach to identify common binding motifs in unrelated proteins.

Conclusion: Our study provides qualitative information about induced fit. These results could be of help for flexible docking.

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Related in: MedlinePlus

Comparison of local rmsd and rmsddev. a) Fragments that are encoded by the same structural letter in the bound and unbound forms. The rmsddev in this case is the rmsdintra, which measures the intrinsic variability of structural letters. b) Fragments that are encoded by different structural letters in the bound and unbound forms, in the case where the structural letter substitution is isolated or at the extremity of a stretch of substitutions. c) Fragments that are encoded by different structural letters in the bound and unbound forms, in the case where the structural letter substitution appears in a stretch of substitution. The red line indicates the equality between local rmsd and rmsddev.
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Figure 3: Comparison of local rmsd and rmsddev. a) Fragments that are encoded by the same structural letter in the bound and unbound forms. The rmsddev in this case is the rmsdintra, which measures the intrinsic variability of structural letters. b) Fragments that are encoded by different structural letters in the bound and unbound forms, in the case where the structural letter substitution is isolated or at the extremity of a stretch of substitutions. c) Fragments that are encoded by different structural letters in the bound and unbound forms, in the case where the structural letter substitution appears in a stretch of substitution. The red line indicates the equality between local rmsd and rmsddev.

Mentions: Structural deformations between bound and unbound forms is usually assessed using classical rmsd computation. In that section, we show a comparison between the assessment of deformation using the structural alphabet and classical rmsd. The measure of deformation using the structural alphabet is given by the rmsddev associated to the structural letter change between bound and unbound forms. For the measure using classical rmsd, we computed local Cα rmsd in a sliding window of four residues along the protein. The reason why we choose a size of four residues for the sliding window is because the structural letters are four-residue long. The results of this comparison on the complex set is shown in Figure 3. In case of identical structural letter in the bound and unbound structure (Figure 3a), we consider the rmsdintra, instead of rmsddev, which is a measure of the intrinsic variability of each structural letter. A few cases of identical structural letters correspond to high local rmsd. These cases correspond to fragments that are surrounded by structural letter substitutions. For example, fragment 64–69 of the R chain of the ligand part of complex 1WQ1 is encoded by QFO in the unbound form and FFE in the bound form. The fragment encoded by the central F has a local rmsd equal to 1.9Å. The case of different structural letter between bound and unbound forms is called a structural letter substitution (Figure 3b and 3c). Here, we further introduce a distinction between isolated substitutions (Figure 3b) and substitutions that appear in stretch (Figure 3c). An isolated substitution denotes a structural letter that is modified when one or both of its neighbors remain unchanged, e.g, ART → ABT or ART → ABG. Inversely, a stretched substitution denotes a structural letter change surrounded by modified structural letters, e. g., ART → CBG. 61% of the structural letter substitutions appear isolated, and 39% appear in stretch. An unexpected finding of this analysis is that some structural letter substitutions exhibit a high rmsddev but a low local rmsd (see Figure 3b and 3c). For example, we observe 534 cases of structural letter substitutions with an associated rmsddev greater than 1 Å and a local rmsd lower than 0.5 Å, out of 1,351 substitutions associated to rmsddev greater than 1 Å (39%). Among 598 isolated substitutions associated with rmsd dev greater than 1 Å, 418 correspond to local rmsd lower than 0.5 Å i. e., 70%. If we consider only stretched substitutions, this ratio is only 15% (116 out of 753). This effect is thus more frequently seen in isolated substitutions than in stretched substitutions. This can be globally assessed by the Pearson correlation coefficient between local rmsd and rmsddev: 0.50 for isolated substitutions and 0.87 for stretched substitutions. These cases correspond to fragments with low rmsd but encoded by highly dissimilar structural letters. They are due to the stochastic nature of the structural encoding using a HMM.


Structural deformation upon protein-protein interaction: a structural alphabet approach.

Martin J, Regad L, Lecornet H, Camproux AC - BMC Struct. Biol. (2008)

Comparison of local rmsd and rmsddev. a) Fragments that are encoded by the same structural letter in the bound and unbound forms. The rmsddev in this case is the rmsdintra, which measures the intrinsic variability of structural letters. b) Fragments that are encoded by different structural letters in the bound and unbound forms, in the case where the structural letter substitution is isolated or at the extremity of a stretch of substitutions. c) Fragments that are encoded by different structural letters in the bound and unbound forms, in the case where the structural letter substitution appears in a stretch of substitution. The red line indicates the equality between local rmsd and rmsddev.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2315654&req=5

Figure 3: Comparison of local rmsd and rmsddev. a) Fragments that are encoded by the same structural letter in the bound and unbound forms. The rmsddev in this case is the rmsdintra, which measures the intrinsic variability of structural letters. b) Fragments that are encoded by different structural letters in the bound and unbound forms, in the case where the structural letter substitution is isolated or at the extremity of a stretch of substitutions. c) Fragments that are encoded by different structural letters in the bound and unbound forms, in the case where the structural letter substitution appears in a stretch of substitution. The red line indicates the equality between local rmsd and rmsddev.
Mentions: Structural deformations between bound and unbound forms is usually assessed using classical rmsd computation. In that section, we show a comparison between the assessment of deformation using the structural alphabet and classical rmsd. The measure of deformation using the structural alphabet is given by the rmsddev associated to the structural letter change between bound and unbound forms. For the measure using classical rmsd, we computed local Cα rmsd in a sliding window of four residues along the protein. The reason why we choose a size of four residues for the sliding window is because the structural letters are four-residue long. The results of this comparison on the complex set is shown in Figure 3. In case of identical structural letter in the bound and unbound structure (Figure 3a), we consider the rmsdintra, instead of rmsddev, which is a measure of the intrinsic variability of each structural letter. A few cases of identical structural letters correspond to high local rmsd. These cases correspond to fragments that are surrounded by structural letter substitutions. For example, fragment 64–69 of the R chain of the ligand part of complex 1WQ1 is encoded by QFO in the unbound form and FFE in the bound form. The fragment encoded by the central F has a local rmsd equal to 1.9Å. The case of different structural letter between bound and unbound forms is called a structural letter substitution (Figure 3b and 3c). Here, we further introduce a distinction between isolated substitutions (Figure 3b) and substitutions that appear in stretch (Figure 3c). An isolated substitution denotes a structural letter that is modified when one or both of its neighbors remain unchanged, e.g, ART → ABT or ART → ABG. Inversely, a stretched substitution denotes a structural letter change surrounded by modified structural letters, e. g., ART → CBG. 61% of the structural letter substitutions appear isolated, and 39% appear in stretch. An unexpected finding of this analysis is that some structural letter substitutions exhibit a high rmsddev but a low local rmsd (see Figure 3b and 3c). For example, we observe 534 cases of structural letter substitutions with an associated rmsddev greater than 1 Å and a local rmsd lower than 0.5 Å, out of 1,351 substitutions associated to rmsddev greater than 1 Å (39%). Among 598 isolated substitutions associated with rmsd dev greater than 1 Å, 418 correspond to local rmsd lower than 0.5 Å i. e., 70%. If we consider only stretched substitutions, this ratio is only 15% (116 out of 753). This effect is thus more frequently seen in isolated substitutions than in stretched substitutions. This can be globally assessed by the Pearson correlation coefficient between local rmsd and rmsddev: 0.50 for isolated substitutions and 0.87 for stretched substitutions. These cases correspond to fragments with low rmsd but encoded by highly dissimilar structural letters. They are due to the stochastic nature of the structural encoding using a HMM.

Bottom Line: Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%).This proportion is even greater in the interface regions (41%).These results could be of help for flexible docking.

View Article: PubMed Central - HTML - PubMed

Affiliation: Equipe de Bioinformatique Génomique et Moléculaire, INSERM UMRS726/Université Denis Diderot Paris 7, F-75005 Paris, France. juliette.martin@jouy.inra.fr

ABSTRACT

Background: In a number of protein-protein complexes, the 3D structures of bound and unbound partners significantly differ, supporting the induced fit hypothesis for protein-protein binding.

Results: In this study, we explore the induced fit modifications on a set of 124 proteins available in both bound and unbound forms, in terms of local structure. The local structure is described thanks to a structural alphabet of 27 structural letters that allows a detailed description of the backbone. Using a control set to distinguish induced fit from experimental error and natural protein flexibility, we show that the fraction of structural letters modified upon binding is significantly greater than in the control set (36% versus 28%). This proportion is even greater in the interface regions (41%). Interface regions preferentially involve coils. Our analysis further reveals that some structural letters in coil are not favored in the interface. We show that certain structural letters in coil are particularly subject to modifications at the interface, and that the severity of structural change also varies. These information are used to derive a structural letter substitution matrix that summarizes the local structural changes observed in our data set. We also illustrate the usefulness of our approach to identify common binding motifs in unrelated proteins.

Conclusion: Our study provides qualitative information about induced fit. These results could be of help for flexible docking.

Show MeSH
Related in: MedlinePlus