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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

Distributions of the rmsd of the p53CTD peptide (Alpha helix: black, Beta sheet: red, disordered: blue) taken from the p53CTD – receptor complex and of the fractions of native binding contacts (fnbc) formed between the receptor and the p53CTD peptide fragment, when the peptide is placed 10 Å away from the binding site.
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f4: Distributions of the rmsd of the p53CTD peptide (Alpha helix: black, Beta sheet: red, disordered: blue) taken from the p53CTD – receptor complex and of the fractions of native binding contacts (fnbc) formed between the receptor and the p53CTD peptide fragment, when the peptide is placed 10 Å away from the binding site.

Mentions: Irrespective of the conformation used (native or non-native), when the peptides are placed at larger distances (20 Å and 30 Å) from the binding sites, their dynamics are characterized by increased flexibility and rapid unfolding and refolding, suggesting that the receptors do not influence their behaviour. However, at 10 Å, the corresponding native bound (alpha helical, beta sheet and disordered) conformations of the p53CTD fluctuated significantly with some unfolding (Fig. 4) yet significantly populated in their corresponding native folded states with the associated native binding contacts (fnbc ~60%). When the native bound conformations of the peptides are replaced by the native conformations seen in the other 2 complexes, folding and unfolding of secondary structures are seen and surprisingly, partial formation of native bound conformations (alpha helix in the case of S100B(ββ) and beta sheet in the case of Sir2) are also observed (Fig. 4). This clearly reflects the long range influence of the receptor on modulating the conformational dynamics of the peptides; native and non-native contacts govern these dynamics.


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

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

Distributions of the rmsd of the p53CTD peptide (Alpha helix: black, Beta sheet: red, disordered: blue) taken from the p53CTD – receptor complex and of the fractions of native binding contacts (fnbc) formed between the receptor and the p53CTD peptide fragment, when the peptide is placed 10 Å away from the binding site.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Distributions of the rmsd of the p53CTD peptide (Alpha helix: black, Beta sheet: red, disordered: blue) taken from the p53CTD – receptor complex and of the fractions of native binding contacts (fnbc) formed between the receptor and the p53CTD peptide fragment, when the peptide is placed 10 Å away from the binding site.
Mentions: Irrespective of the conformation used (native or non-native), when the peptides are placed at larger distances (20 Å and 30 Å) from the binding sites, their dynamics are characterized by increased flexibility and rapid unfolding and refolding, suggesting that the receptors do not influence their behaviour. However, at 10 Å, the corresponding native bound (alpha helical, beta sheet and disordered) conformations of the p53CTD fluctuated significantly with some unfolding (Fig. 4) yet significantly populated in their corresponding native folded states with the associated native binding contacts (fnbc ~60%). When the native bound conformations of the peptides are replaced by the native conformations seen in the other 2 complexes, folding and unfolding of secondary structures are seen and surprisingly, partial formation of native bound conformations (alpha helix in the case of S100B(ββ) and beta sheet in the case of Sir2) are also observed (Fig. 4). This clearly reflects the long range influence of the receptor on modulating the conformational dynamics of the peptides; native and non-native contacts govern these dynamics.

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