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Probing Difference in Binding Modes of Inhibitors to MDMX by Molecular Dynamics Simulations and Different Free Energy Methods.

Shi S, Zhang S, Zhang Q - PLoS ONE (2015)

Bottom Line: The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years.The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors.The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions.

View Article: PubMed Central - PubMed

Affiliation: School of Science, Shandong Jianzhu University, Jinan, China.

ABSTRACT
The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years. This current work adopted molecular dynamics (MD) simulations and cross-correlation analysis to investigate conformation changes of MDMX caused by inhibitor bindings. The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors. Two different methods of binding free energy predictions were employed to carry out a comparable insight into binding mechanisms of four inhibitors PMI, pDI, WK23 and WW8 to MDMX. The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions. The binding free energies were further divided into contribution of each residue and the derived information gives a conclusion that the hydrophobic interactions, such as CH-CH, CH-π and π-π interactions, are responsible for the inhibitor associations with MDMX.

No MeSH data available.


Related in: MedlinePlus

Comparison of the eigenvalues plotted against the corresponding eigenvector index obtained from the covariance matrix of Cα atoms constructed from the equilibrium of MD simulations.
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pone.0141409.g005: Comparison of the eigenvalues plotted against the corresponding eigenvector index obtained from the covariance matrix of Cα atoms constructed from the equilibrium of MD simulations.

Mentions: To evaluate the overall effect of inhibitor associations on the flexibility of MDMX, the eigenvalues were obtained by diagonalizing the covariance matrix constructed by the atomic coordinate[78, 79] and the information was displayed in Fig 5. The first several eigenvalues indicate the concerted motions of residues. It is observed that these eigenvalues quickly reduce in amplitude to reach a number of constrained and more localized movement. The first six principal components contribute up to 58.2%, 59.8%, 61.4% and 69.4% in the total motions for the PMI-MDMX, pDI-MDMX, WK23-MDMX and WW8-MDMX compounds, respectively. This result suggests that the bindings of different structural inhibitors produce different effects on the concerted motions of MDMX. The above analyses basically agree with the previous studies[29, 30, 60].


Probing Difference in Binding Modes of Inhibitors to MDMX by Molecular Dynamics Simulations and Different Free Energy Methods.

Shi S, Zhang S, Zhang Q - PLoS ONE (2015)

Comparison of the eigenvalues plotted against the corresponding eigenvector index obtained from the covariance matrix of Cα atoms constructed from the equilibrium of MD simulations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4625964&req=5

pone.0141409.g005: Comparison of the eigenvalues plotted against the corresponding eigenvector index obtained from the covariance matrix of Cα atoms constructed from the equilibrium of MD simulations.
Mentions: To evaluate the overall effect of inhibitor associations on the flexibility of MDMX, the eigenvalues were obtained by diagonalizing the covariance matrix constructed by the atomic coordinate[78, 79] and the information was displayed in Fig 5. The first several eigenvalues indicate the concerted motions of residues. It is observed that these eigenvalues quickly reduce in amplitude to reach a number of constrained and more localized movement. The first six principal components contribute up to 58.2%, 59.8%, 61.4% and 69.4% in the total motions for the PMI-MDMX, pDI-MDMX, WK23-MDMX and WW8-MDMX compounds, respectively. This result suggests that the bindings of different structural inhibitors produce different effects on the concerted motions of MDMX. The above analyses basically agree with the previous studies[29, 30, 60].

Bottom Line: The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years.The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors.The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions.

View Article: PubMed Central - PubMed

Affiliation: School of Science, Shandong Jianzhu University, Jinan, China.

ABSTRACT
The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years. This current work adopted molecular dynamics (MD) simulations and cross-correlation analysis to investigate conformation changes of MDMX caused by inhibitor bindings. The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors. Two different methods of binding free energy predictions were employed to carry out a comparable insight into binding mechanisms of four inhibitors PMI, pDI, WK23 and WW8 to MDMX. The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions. The binding free energies were further divided into contribution of each residue and the derived information gives a conclusion that the hydrophobic interactions, such as CH-CH, CH-π and π-π interactions, are responsible for the inhibitor associations with MDMX.

No MeSH data available.


Related in: MedlinePlus