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Long range recognition and selection in IDPs: the interactions of the C-terminus of p53.

Kannan S, Lane DP, Verma CS - Sci Rep (2016)

Bottom Line: The C-terminal domain of p53 is an extensively studied IDP, interacting with different partners through multiple distinct conformations.We find that the free peptide segment rapidly interconverts between ordered and disordered states with significant populations of the conformations that are seen in the complexed states.The underlying global folding-binding landscape points to a synergistic mechanism in which recognition is dictated via long range electrostatic recognition which results in the formation of reactive structures as far away as 10 Å, and binding proceeds with the steering of selected conformations followed by induced folding at the target surface or within a close range.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671.

ABSTRACT
The C-terminal domain of p53 is an extensively studied IDP, interacting with different partners through multiple distinct conformations. To explore the interplay between preformed structural elements and intrinsic fluctuations in its folding and binding we combine extensive atomistic equilibrium and non-equilibrium simulations. We find that the free peptide segment rapidly interconverts between ordered and disordered states with significant populations of the conformations that are seen in the complexed states. The underlying global folding-binding landscape points to a synergistic mechanism in which recognition is dictated via long range electrostatic recognition which results in the formation of reactive structures as far away as 10 Å, and binding proceeds with the steering of selected conformations followed by induced folding at the target surface or within a close range.

No MeSH data available.


Related in: MedlinePlus

Average rmsf of only the binding site residues of the structural ensemble of three different p53CTD binding receptors, with the peptide in its native and non-native conformation bound with the receptor at the binding site and at various distances from the binding site.
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f6: Average rmsf of only the binding site residues of the structural ensemble of three different p53CTD binding receptors, with the peptide in its native and non-native conformation bound with the receptor at the binding site and at various distances from the binding site.

Mentions: Although the receptors remain stable overall, irrespective of the bound conformations of the peptides, and of their separation from the peptides (10, 20 and 30 Å), varying patterns of fluctuations of residues in and around the binding sites were observed. When the peptide is bound, the binding pocket residues do not fluctuate much, and if the peptide is in its native conformation, then the fluctuations of the binding site residues are the lowest (Fig. 6). However surprisingly, these fluctuations increase when the peptide is between 10 and 20 Å after which they get attenuated. This pattern is observed for residues in the binding pocket that either make direct contacts with the peptide in its bound state or are not specific, thus suggesting that recognition begins to occur at distances between 10–20 Å.


Long range recognition and selection in IDPs: the interactions of the C-terminus of p53.

Kannan S, Lane DP, Verma CS - Sci Rep (2016)

Average rmsf of only the binding site residues of the structural ensemble of three different p53CTD binding receptors, with the peptide in its native and non-native conformation bound with the receptor at the binding site and at various distances from the binding site.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814905&req=5

f6: Average rmsf of only the binding site residues of the structural ensemble of three different p53CTD binding receptors, with the peptide in its native and non-native conformation bound with the receptor at the binding site and at various distances from the binding site.
Mentions: Although the receptors remain stable overall, irrespective of the bound conformations of the peptides, and of their separation from the peptides (10, 20 and 30 Å), varying patterns of fluctuations of residues in and around the binding sites were observed. When the peptide is bound, the binding pocket residues do not fluctuate much, and if the peptide is in its native conformation, then the fluctuations of the binding site residues are the lowest (Fig. 6). However surprisingly, these fluctuations increase when the peptide is between 10 and 20 Å after which they get attenuated. This pattern is observed for residues in the binding pocket that either make direct contacts with the peptide in its bound state or are not specific, thus suggesting that recognition begins to occur at distances between 10–20 Å.

Bottom Line: The C-terminal domain of p53 is an extensively studied IDP, interacting with different partners through multiple distinct conformations.We find that the free peptide segment rapidly interconverts between ordered and disordered states with significant populations of the conformations that are seen in the complexed states.The underlying global folding-binding landscape points to a synergistic mechanism in which recognition is dictated via long range electrostatic recognition which results in the formation of reactive structures as far away as 10 Å, and binding proceeds with the steering of selected conformations followed by induced folding at the target surface or within a close range.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671.

ABSTRACT
The C-terminal domain of p53 is an extensively studied IDP, interacting with different partners through multiple distinct conformations. To explore the interplay between preformed structural elements and intrinsic fluctuations in its folding and binding we combine extensive atomistic equilibrium and non-equilibrium simulations. We find that the free peptide segment rapidly interconverts between ordered and disordered states with significant populations of the conformations that are seen in the complexed states. The underlying global folding-binding landscape points to a synergistic mechanism in which recognition is dictated via long range electrostatic recognition which results in the formation of reactive structures as far away as 10 Å, and binding proceeds with the steering of selected conformations followed by induced folding at the target surface or within a close range.

No MeSH data available.


Related in: MedlinePlus