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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.


MDM2 and MDMX are displayed in surface modes, inhibitors in cartoon modes and Leu26′ in stick modes.(A) for the pDI6W-MDM2 complex, (B) for the pDI6W-MDMX complex, (C) for the pDIQ-MDM2 complex and (D) for the pDIQ-MDMX complex.
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f9: MDM2 and MDMX are displayed in surface modes, inhibitors in cartoon modes and Leu26′ in stick modes.(A) for the pDI6W-MDM2 complex, (B) for the pDI6W-MDMX complex, (C) for the pDIQ-MDM2 complex and (D) for the pDIQ-MDMX complex.

Mentions: The above analyses suggest that the conformations of M53 and Y99 in MDMX are highly different from the one of L54 and Y99 in MDM2. The surface mode display of MDM2/MDMX (Fig. 9) structurally reveal that how these conformational difference affect the inhibitor bindings. By comparison of Fig. 9B,D with Fig. 9A,C, the long sidechain of M53 and the phenol of Y99 form two humps toward the residues L26′, which results in a potential steric clash with the residue L26′ and prevents L26′ from reaching the deep of the hydrophobic groove formed by the helix α2 and the helix α4 in MDMX (Fig. 1A). Thus, this potential steric clash reduces the number of van der Waals contacts of L26′ with the hydrophobic residues in the binding groove of MDMX.


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)

MDM2 and MDMX are displayed in surface modes, inhibitors in cartoon modes and Leu26′ in stick modes.(A) for the pDI6W-MDM2 complex, (B) for the pDI6W-MDMX complex, (C) for the pDIQ-MDM2 complex and (D) for the pDIQ-MDMX complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f9: MDM2 and MDMX are displayed in surface modes, inhibitors in cartoon modes and Leu26′ in stick modes.(A) for the pDI6W-MDM2 complex, (B) for the pDI6W-MDMX complex, (C) for the pDIQ-MDM2 complex and (D) for the pDIQ-MDMX complex.
Mentions: The above analyses suggest that the conformations of M53 and Y99 in MDMX are highly different from the one of L54 and Y99 in MDM2. The surface mode display of MDM2/MDMX (Fig. 9) structurally reveal that how these conformational difference affect the inhibitor bindings. By comparison of Fig. 9B,D with Fig. 9A,C, the long sidechain of M53 and the phenol of Y99 form two humps toward the residues L26′, which results in a potential steric clash with the residue L26′ and prevents L26′ from reaching the deep of the hydrophobic groove formed by the helix α2 and the helix α4 in MDMX (Fig. 1A). Thus, this potential steric clash reduces the number of van der Waals contacts of L26′ with the hydrophobic residues in the binding groove of MDMX.

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.