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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 RMSF of Cα atoms in MDMX and MDM2 through the equilibrium phase of MD simulation.(A) for the inhibitor pDI6W and (B) for the inhibitor pDIQ.
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f5: The RMSF of Cα atoms in MDMX and MDM2 through the equilibrium phase of MD simulation.(A) for the inhibitor pDI6W and (B) for the inhibitor pDIQ.

Mentions: To quantitatively measure the mean backbone flexibility of separate residues, the RMSF values of Cα atoms in MDM2/MDMX were calculated using the equilibrium trajectory, as shown in Fig. 5. The results suggest that the mobility of the loop L3 (the residues 76–79), L5 (the residues 93–96) and the helix α4 domain (the residues 97–108) in MDMX is stronger than that in MDM2. Additionally, the domains near the residues M53 and Y66 in MDMX also produce greater flexibility relative to the corresponding domains in MDM2. The residues involving the decrease of the inhibitor-residue interactions in MDMX relative to MDM2 are located in the above domains, which shows that the changes in the inhibitor-residue interactions can significantly affect the mobility of proteins.


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 RMSF of Cα atoms in MDMX and MDM2 through the equilibrium phase of MD simulation.(A) for the inhibitor pDI6W and (B) for the inhibitor pDIQ.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: The RMSF of Cα atoms in MDMX and MDM2 through the equilibrium phase of MD simulation.(A) for the inhibitor pDI6W and (B) for the inhibitor pDIQ.
Mentions: To quantitatively measure the mean backbone flexibility of separate residues, the RMSF values of Cα atoms in MDM2/MDMX were calculated using the equilibrium trajectory, as shown in Fig. 5. The results suggest that the mobility of the loop L3 (the residues 76–79), L5 (the residues 93–96) and the helix α4 domain (the residues 97–108) in MDMX is stronger than that in MDM2. Additionally, the domains near the residues M53 and Y66 in MDMX also produce greater flexibility relative to the corresponding domains in MDM2. The residues involving the decrease of the inhibitor-residue interactions in MDMX relative to MDM2 are located in the above domains, which shows that the changes in the inhibitor-residue interactions can significantly affect the mobility of proteins.

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.