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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

Contribution of Electrostatics and Van der Waals to the total binding free energy of three p53CTD peptide – receptor complexes.All the conformations sampled during USMD simulations with bound form p53CTD fragment either in its native and non-native conformations at the binding site and various distances from the binding site are included in the binding energy calculations.
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f8: Contribution of Electrostatics and Van der Waals to the total binding free energy of three p53CTD peptide – receptor complexes.All the conformations sampled during USMD simulations with bound form p53CTD fragment either in its native and non-native conformations at the binding site and various distances from the binding site are included in the binding energy calculations.

Mentions: To characterize the energetics associated with the process of coupled binding and folding, we carried out MMPBSA and MMGBSA type binding energy calculations on the ensembles, generated by the USMD simulations. In all the simulated complexes, when the peptide was positioned at distances far from the binding site (20 Å and 30 Å), irrespective of the conformation that the peptide adopts, the total binding energy was low suggesting little influence of the two molecules on each other (Fig. 7). However at a distance of 10 Å from the binding sites, the total binding energy favored the association/complexation process in all the simulations (Fig. 7). Again at the binding interface, the formation of receptor–peptide complex is highly energetically favored, with the native complexes clearly favored. Interestingly such a clear preference for the native conformations of the peptides was apparent even at 10 Å (Fig. 7). Both the electrostatics and van der Waals components begin to contribute at 10 Å from the binding site (Fig. 8) although, as expected, the long range component i.e. the electrostatics dominated (however when we factor in the desolvation penalties (Fig. S10), the magnitude of electrostatic contributions is attenuated); and this component was strongest only when the peptide was in its native conformation. At the binding site, the complexation is energetically more favored with the native bound conformation of the peptide with both electrostatics and VdW making up the binding energy; as expected, the contribution of VdW is much more than it is at 10 Å. This is not surprising since the binding is accompanied by conformational rearrangements for better/tight packing and stabilization of the complex structure. Our USMD simulations of the receptor–peptide complexation suggest that each receptor preferentially binds to p53CTD in which structural elements that resemble the bound state exist, ie, through an extended conformational selection mechanism. A point to note is that our electrostatic interactions were evaluated without including the effects of salt; however estimates of the salt effects (data not shown) show that the patterns of changes across the systems remain similar to the no-salt case; the interactions are attenuated only slightly.


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

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

Contribution of Electrostatics and Van der Waals to the total binding free energy of three p53CTD peptide – receptor complexes.All the conformations sampled during USMD simulations with bound form p53CTD fragment either in its native and non-native conformations at the binding site and various distances from the binding site are included in the binding energy calculations.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Contribution of Electrostatics and Van der Waals to the total binding free energy of three p53CTD peptide – receptor complexes.All the conformations sampled during USMD simulations with bound form p53CTD fragment either in its native and non-native conformations at the binding site and various distances from the binding site are included in the binding energy calculations.
Mentions: To characterize the energetics associated with the process of coupled binding and folding, we carried out MMPBSA and MMGBSA type binding energy calculations on the ensembles, generated by the USMD simulations. In all the simulated complexes, when the peptide was positioned at distances far from the binding site (20 Å and 30 Å), irrespective of the conformation that the peptide adopts, the total binding energy was low suggesting little influence of the two molecules on each other (Fig. 7). However at a distance of 10 Å from the binding sites, the total binding energy favored the association/complexation process in all the simulations (Fig. 7). Again at the binding interface, the formation of receptor–peptide complex is highly energetically favored, with the native complexes clearly favored. Interestingly such a clear preference for the native conformations of the peptides was apparent even at 10 Å (Fig. 7). Both the electrostatics and van der Waals components begin to contribute at 10 Å from the binding site (Fig. 8) although, as expected, the long range component i.e. the electrostatics dominated (however when we factor in the desolvation penalties (Fig. S10), the magnitude of electrostatic contributions is attenuated); and this component was strongest only when the peptide was in its native conformation. At the binding site, the complexation is energetically more favored with the native bound conformation of the peptide with both electrostatics and VdW making up the binding energy; as expected, the contribution of VdW is much more than it is at 10 Å. This is not surprising since the binding is accompanied by conformational rearrangements for better/tight packing and stabilization of the complex structure. Our USMD simulations of the receptor–peptide complexation suggest that each receptor preferentially binds to p53CTD in which structural elements that resemble the bound state exist, ie, through an extended conformational selection mechanism. A point to note is that our electrostatic interactions were evaluated without including the effects of salt; however estimates of the salt effects (data not shown) show that the patterns of changes across the systems remain similar to the no-salt case; the interactions are attenuated only slightly.

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