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Conformational ensembles explored dynamically from disordered peptides targeting chemokine receptor CXCR4.

Vincenzi M, Costantini S, Scala S, Tesauro D, Accardo A, Leone M, Colonna G, Guillon J, Portella L, Trotta AM, Ronga L, Rossi F - Int J Mol Sci (2015)

Bottom Line: These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles.They revealed a network of transient and dynamic H-bonds and interactions with water molecules.Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy University of Naples "Federico II", and CIRPeB, Via Mezzocannone 16, I-80134 Naples, Italy. marian.vincenzi@unina.it.

ABSTRACT
This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target.

No MeSH data available.


Related in: MedlinePlus

Analysis of the molecular dynamics simulations performed on PepE (in black) and PepK (in grey) at physiological pH in explicit solvent in terms of: (A) root mean square deviation (RMSD) plot; (B) root mean square fluctuation (RMSF); (C) gyration radius plot; and (D) H-bonds plot.
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ijms-16-12159-f004: Analysis of the molecular dynamics simulations performed on PepE (in black) and PepK (in grey) at physiological pH in explicit solvent in terms of: (A) root mean square deviation (RMSD) plot; (B) root mean square fluctuation (RMSF); (C) gyration radius plot; and (D) H-bonds plot.

Mentions: Molecular dynamics simulations were performed on the two peptides, which were linearly modeled as reported in the Material and Methods Section, at neutral pH. In Figure 4A, we show the plots of the Root Mean Square Deviation (RMSD), computed by overlapping the various structures during simulations in respect to the initial conformation. RMSD plots of PepK and PepE evidence high levels of fluctuation, thus suggesting that these peptides are flexible. On the one hand, this result is confirmed also by Root Mean Square Fluctuation (RMSF) plots where the residues located at N- and C-termini present higher values of RMSF (Figure 4B). Instead, the gyration radii decreased during the simulations (Figure 4C) reaching a value of 0.5 nm. This suggests an increasing compactness of the two peptides, which result as if they were stabilized by a certain number of H-bonds of main chain–main chain (MM), main chain–side chain (MS) and side chain–side chain (SS) types (Figure 4D). For this reason, the two peptides tended to become more compact and the radius of gyration decreased. According to the data obtained by CD and NMR measurements in aqueous solution, the analysis of the secondary structure evolution clearly showed the high flexibility of both peptides during the simulations, which makes difficult the formation of stable regular secondary structure elements, i.e., helix and β-strand. Very flexible peptide structure are normally characterized by several conformers at equilibrium, hence they could be well described by a conformational ensemble. Having taken this property into proper account, we have firstly performed a cluster analysis to determine the groups of structures that share similar conformational features according to their RMSD values.


Conformational ensembles explored dynamically from disordered peptides targeting chemokine receptor CXCR4.

Vincenzi M, Costantini S, Scala S, Tesauro D, Accardo A, Leone M, Colonna G, Guillon J, Portella L, Trotta AM, Ronga L, Rossi F - Int J Mol Sci (2015)

Analysis of the molecular dynamics simulations performed on PepE (in black) and PepK (in grey) at physiological pH in explicit solvent in terms of: (A) root mean square deviation (RMSD) plot; (B) root mean square fluctuation (RMSF); (C) gyration radius plot; and (D) H-bonds plot.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490436&req=5

ijms-16-12159-f004: Analysis of the molecular dynamics simulations performed on PepE (in black) and PepK (in grey) at physiological pH in explicit solvent in terms of: (A) root mean square deviation (RMSD) plot; (B) root mean square fluctuation (RMSF); (C) gyration radius plot; and (D) H-bonds plot.
Mentions: Molecular dynamics simulations were performed on the two peptides, which were linearly modeled as reported in the Material and Methods Section, at neutral pH. In Figure 4A, we show the plots of the Root Mean Square Deviation (RMSD), computed by overlapping the various structures during simulations in respect to the initial conformation. RMSD plots of PepK and PepE evidence high levels of fluctuation, thus suggesting that these peptides are flexible. On the one hand, this result is confirmed also by Root Mean Square Fluctuation (RMSF) plots where the residues located at N- and C-termini present higher values of RMSF (Figure 4B). Instead, the gyration radii decreased during the simulations (Figure 4C) reaching a value of 0.5 nm. This suggests an increasing compactness of the two peptides, which result as if they were stabilized by a certain number of H-bonds of main chain–main chain (MM), main chain–side chain (MS) and side chain–side chain (SS) types (Figure 4D). For this reason, the two peptides tended to become more compact and the radius of gyration decreased. According to the data obtained by CD and NMR measurements in aqueous solution, the analysis of the secondary structure evolution clearly showed the high flexibility of both peptides during the simulations, which makes difficult the formation of stable regular secondary structure elements, i.e., helix and β-strand. Very flexible peptide structure are normally characterized by several conformers at equilibrium, hence they could be well described by a conformational ensemble. Having taken this property into proper account, we have firstly performed a cluster analysis to determine the groups of structures that share similar conformational features according to their RMSD values.

Bottom Line: These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles.They revealed a network of transient and dynamic H-bonds and interactions with water molecules.Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy University of Naples "Federico II", and CIRPeB, Via Mezzocannone 16, I-80134 Naples, Italy. marian.vincenzi@unina.it.

ABSTRACT
This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target.

No MeSH data available.


Related in: MedlinePlus