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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 Chi1 (χ1, in degree) dihedral angle of the side chain of Y100 in MDM2 and Y99 in MDMX as a function of time and frequency distribution: (A,B) for the pDI6W-MDM2/MDMX complexes, (C,D) for the pDIQ-MDM2/MDMX complexes.
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f6: The Chi1 (χ1, in degree) dihedral angle of the side chain of Y100 in MDM2 and Y99 in MDMX as a function of time and frequency distribution: (A,B) for the pDI6W-MDM2/MDMX complexes, (C,D) for the pDIQ-MDM2/MDMX complexes.

Mentions: The inhibitor-Y99 interaction in MDMX is stronger than the inhibitor-Y100 interaction in MDM2. To reveal the reason of this change, the time evolution of the Chi1 (χ1) dihedral angle of the sidechain in Y99 (MDMX) and Y100 (MDM2) and their frequency distribution were calculated through the polarizable MD simulation (shown in Fig. 6). One can observe that the mobility of the side chain of Y99 is much stronger than that of Y100 (Fig. 6A,C). According to Fig. 6B,D, the frequency distribution of Chi1 dihedral angle of Y99 is located near 286°, while that of Y100 around 186°. This result shows that the orientation of the side chain for Y99 in MDMX is highly different from that of the side chain for Y100 in MDM2, which may significantly affect the inhibitor bindings.


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 Chi1 (χ1, in degree) dihedral angle of the side chain of Y100 in MDM2 and Y99 in MDMX as a function of time and frequency distribution: (A,B) for the pDI6W-MDM2/MDMX complexes, (C,D) for the pDIQ-MDM2/MDMX complexes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: The Chi1 (χ1, in degree) dihedral angle of the side chain of Y100 in MDM2 and Y99 in MDMX as a function of time and frequency distribution: (A,B) for the pDI6W-MDM2/MDMX complexes, (C,D) for the pDIQ-MDM2/MDMX complexes.
Mentions: The inhibitor-Y99 interaction in MDMX is stronger than the inhibitor-Y100 interaction in MDM2. To reveal the reason of this change, the time evolution of the Chi1 (χ1) dihedral angle of the sidechain in Y99 (MDMX) and Y100 (MDM2) and their frequency distribution were calculated through the polarizable MD simulation (shown in Fig. 6). One can observe that the mobility of the side chain of Y99 is much stronger than that of Y100 (Fig. 6A,C). According to Fig. 6B,D, the frequency distribution of Chi1 dihedral angle of Y99 is located near 286°, while that of Y100 around 186°. This result shows that the orientation of the side chain for Y99 in MDMX is highly different from that of the side chain for Y100 in MDM2, which may significantly affect the inhibitor bindings.

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.