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Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation.

Chen J, Wang J, Zhang Q, Chen K, Zhu W - Sci Rep (2015)

Bottom Line: Binding abilities of current inhibitors to MDMX are weaker than to MDM2.The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX.The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98.

View Article: PubMed Central - PubMed

Affiliation: School of Science, Shandong Jiaotong University, Jinan, 250014, China.

ABSTRACT
Binding abilities of current inhibitors to MDMX are weaker than to MDM2. Polarizable molecular dynamics simulations (MD) followed by Quantum mechanics/molecular mechanics generalized Born surface area (QM//MM-GBSA) calculations were performed to investigate the binding difference of inhibitors to MDM2 and MDMX. The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX. The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98. The calculated results using the residue-based free energy decomposition method further prove that the interaction strength of inhibitors with M53, V92, P95 and L98 from MDMX are obviously reduced compared to MDM2. We expect that this study can provide significant theoretical guidance for designs of potent dual inhibitors to block the p53-MDM2/MDMX interactions.

No MeSH data available.


The inhibitor-residue interaction spectra: (A) the pDI6W-MDM2 complex, (B) the pDI6W-MDMX complex, (C) the pDIQ-MDM2 complex and (D) the pDIQ-MDMX complex.
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f3: The inhibitor-residue interaction spectra: (A) the pDI6W-MDM2 complex, (B) the pDI6W-MDMX complex, (C) the pDIQ-MDM2 complex and (D) the pDIQ-MDMX complex.

Mentions: To further explore the origin of weaker binding of inhibitors to MDMX than to MDM2, the inhibitor-residue interaction were calculated by using the residue-based free energy decomposition method and the results depicted in Fig. 3. The relative positions of the residues involving important contributions in the complexes were described in Fig. 4 by using the lowest energy structure from the polarizable MD trajectory. The information of hydrogen bonds from the Cpptraj analysis was listed in Table 3.


Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation.

Chen J, Wang J, Zhang Q, Chen K, Zhu W - Sci Rep (2015)

The inhibitor-residue interaction spectra: (A) the pDI6W-MDM2 complex, (B) the pDI6W-MDMX complex, (C) the pDIQ-MDM2 complex and (D) the pDIQ-MDMX complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663504&req=5

f3: The inhibitor-residue interaction spectra: (A) the pDI6W-MDM2 complex, (B) the pDI6W-MDMX complex, (C) the pDIQ-MDM2 complex and (D) the pDIQ-MDMX complex.
Mentions: To further explore the origin of weaker binding of inhibitors to MDMX than to MDM2, the inhibitor-residue interaction were calculated by using the residue-based free energy decomposition method and the results depicted in Fig. 3. The relative positions of the residues involving important contributions in the complexes were described in Fig. 4 by using the lowest energy structure from the polarizable MD trajectory. The information of hydrogen bonds from the Cpptraj analysis was listed in Table 3.

Bottom Line: Binding abilities of current inhibitors to MDMX are weaker than to MDM2.The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX.The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98.

View Article: PubMed Central - PubMed

Affiliation: School of Science, Shandong Jiaotong University, Jinan, 250014, China.

ABSTRACT
Binding abilities of current inhibitors to MDMX are weaker than to MDM2. Polarizable molecular dynamics simulations (MD) followed by Quantum mechanics/molecular mechanics generalized Born surface area (QM//MM-GBSA) calculations were performed to investigate the binding difference of inhibitors to MDM2 and MDMX. The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX. The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98. The calculated results using the residue-based free energy decomposition method further prove that the interaction strength of inhibitors with M53, V92, P95 and L98 from MDMX are obviously reduced compared to MDM2. We expect that this study can provide significant theoretical guidance for designs of potent dual inhibitors to block the p53-MDM2/MDMX interactions.

No MeSH data available.