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. 2015 Oct 29;10(10):e0141409.
doi: 10.1371/journal.pone.0141409. eCollection 2015.

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

Shuhua Shi  1 , Shaolong Zhang  2 , Qinggang Zhang  2
Affiliations

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

Shuhua Shi et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Molecular structures of the inhibitors: (A) PMI, (B) pDI, (C) WK23 and (D) WW8.
Fig 2
Fig 2. RMSD values of the backbone atoms relative to the initial minimized structures as functions of simulation time.
Fig 3
Fig 3. RMSF of Cα atoms in MDMX through the equilibrium phase of MD simulations.
Fig 4
Fig 4. Cross-correlation matrices of the fluctuations of the coordinates for Cα atoms of MDMX around their mean positions during the equilibrium phase of simulations.
The extents of correlated motions and anticorrelated motions are color-coded for four binding complexes: A for PMI-MDMX, B for pDI-MDMX, C for WK23-MDMX and D for WW8-MDMX.
Fig 5
Fig 5. 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.
Fig 6
Fig 6. The interaction spectra of the separate residues of MDMX with the inhibitors: (A) PMI, (B) pDI, (C) WK23 and (D) WW8.
Fig 7
Fig 7. Geometries of key residues, which produce favorable interactions with the inhibitors, are depicted in the complexes according to the lowest energy structure from MD trajectory.
(A) PMI-MDMX, (B)pDI-MDMX, (C) WK23-MDMX and (D) WW8-MDMX.
See this image and copyright information in PMC

References

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