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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 L54 in MDM2 and M53 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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f8: The Chi1 (χ1, in degree) dihedral angle of the side chain of L54 in MDM2 and M53 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 residue L54 in MDM2 is substituted by M53 in MDMX and the length of the side chain of M53 is longer than the one of L54. To reveal how this change affect the inhibitor bindings, the time evolution of the Chi1 (χ1) dihedral angle of the side chain in M53 and L54 were calculated through the MD trajectory, as well as their frequency distribution were depicted in Fig. 8. The Chi1 (χ1) dihedral angle of M53 are much different from that of L54 during MD simulation. The Chi1 angle of L54 fluctuates around 285°, while the one of M53 frequently changes between two different states. The two peak values of the frequency distributions of M53 in the MDMX binding complexes are located in 195.4° and 286.2° respectively, while the single peak values of L54 in the MDM2 binding complexes are in 285.3°. In the MDMX binding complex, the population of the Chi1 for 195.4° is more than that of 286.2°. This result shows that the orientation of the side chain of M53 highly differs from the one of L54, which may produce significant effect on the inhibitor bindings. The free energy landscapes were constructed by using the backbone ψ and φ angle of M53 and L54 and plotted in Figure S5. The results indicate that the backbone ψ and φ angle of M53 hardly changes compared to that of L54.


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 L54 in MDM2 and M53 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

f8: The Chi1 (χ1, in degree) dihedral angle of the side chain of L54 in MDM2 and M53 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 residue L54 in MDM2 is substituted by M53 in MDMX and the length of the side chain of M53 is longer than the one of L54. To reveal how this change affect the inhibitor bindings, the time evolution of the Chi1 (χ1) dihedral angle of the side chain in M53 and L54 were calculated through the MD trajectory, as well as their frequency distribution were depicted in Fig. 8. The Chi1 (χ1) dihedral angle of M53 are much different from that of L54 during MD simulation. The Chi1 angle of L54 fluctuates around 285°, while the one of M53 frequently changes between two different states. The two peak values of the frequency distributions of M53 in the MDMX binding complexes are located in 195.4° and 286.2° respectively, while the single peak values of L54 in the MDM2 binding complexes are in 285.3°. In the MDMX binding complex, the population of the Chi1 for 195.4° is more than that of 286.2°. This result shows that the orientation of the side chain of M53 highly differs from the one of L54, which may produce significant effect on the inhibitor bindings. The free energy landscapes were constructed by using the backbone ψ and φ angle of M53 and L54 and plotted in Figure S5. The results indicate that the backbone ψ and φ angle of M53 hardly changes compared to that of L54.

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.