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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.


Superimposed structures of inhibitor-MDM2 complex and inhibitor-MDMX complex.MDM2/MDMX and inhibitors are shown in cartoon modes and the key residues in stick modes, MDM2 is displayed in light blue and MDMX in orange.
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f10: Superimposed structures of inhibitor-MDM2 complex and inhibitor-MDMX complex.MDM2/MDMX and inhibitors are shown in cartoon modes and the key residues in stick modes, MDM2 is displayed in light blue and MDMX in orange.

Mentions: The above dihedral analyses suggest that the Chi1 angle of Tyr100 in MDM2 is about 186°, while the one of Y99 in MDMX is about 286°. The longer sidechain of M53 in MDMX relative to L54 in MDM2 points to the outside of the binding groove. To clearly clarify this difference, the structural superimposition analyses of MDM2 and MDMX were performed by using the lowest energy structure extracted from MD trajectory and depicted in Fig. 10. One can observe that the phenyl of Y100 flips away from the binding pocket and the residue L54 in the MDM2 (Fig. 10A,C). This orientation shows that the binding cleft of MDM2 shapes an open state, which allows L26′ and inhibitors to go into the deep of the cleft. Thus, L26′ can produce strong interactions with L54, V93, H96 and I99. However, the sidechains of M53 and Y99 in MDMX protrude into the binding groove, blocking a part of the cleft on its opposite sides and making the hydrophobic cleft smaller (Fig. 10B,D). This structural rearrangement of M53 and Y99 forms a closed conformation in MDMX, preventing the inhibitors and L26′ from reaching the deep of the binding cleft. Thus the van der Walls interactions of inhibitors with M53, V92, P95 and L98 in the hydrophobic groove of MDMX are reduced relative to that of inhibitors with the corresponding residues in MDM2, which agrees well with the analysis of the inhibitor-residue interactions. Overall, a conclusion can be obtained that the closed conformations of the binding cleft adopted by MDMX is the origin of weaker bindings of inhibitors to MDMX than to MDM2. Studies from Phan and Popowicz et al. also suggested that special conformation of M53 and Y99 leads to a steric clash with inhibitors, which agrees with our current results1977.


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)

Superimposed structures of inhibitor-MDM2 complex and inhibitor-MDMX complex.MDM2/MDMX and inhibitors are shown in cartoon modes and the key residues in stick modes, MDM2 is displayed in light blue and MDMX in orange.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f10: Superimposed structures of inhibitor-MDM2 complex and inhibitor-MDMX complex.MDM2/MDMX and inhibitors are shown in cartoon modes and the key residues in stick modes, MDM2 is displayed in light blue and MDMX in orange.
Mentions: The above dihedral analyses suggest that the Chi1 angle of Tyr100 in MDM2 is about 186°, while the one of Y99 in MDMX is about 286°. The longer sidechain of M53 in MDMX relative to L54 in MDM2 points to the outside of the binding groove. To clearly clarify this difference, the structural superimposition analyses of MDM2 and MDMX were performed by using the lowest energy structure extracted from MD trajectory and depicted in Fig. 10. One can observe that the phenyl of Y100 flips away from the binding pocket and the residue L54 in the MDM2 (Fig. 10A,C). This orientation shows that the binding cleft of MDM2 shapes an open state, which allows L26′ and inhibitors to go into the deep of the cleft. Thus, L26′ can produce strong interactions with L54, V93, H96 and I99. However, the sidechains of M53 and Y99 in MDMX protrude into the binding groove, blocking a part of the cleft on its opposite sides and making the hydrophobic cleft smaller (Fig. 10B,D). This structural rearrangement of M53 and Y99 forms a closed conformation in MDMX, preventing the inhibitors and L26′ from reaching the deep of the binding cleft. Thus the van der Walls interactions of inhibitors with M53, V92, P95 and L98 in the hydrophobic groove of MDMX are reduced relative to that of inhibitors with the corresponding residues in MDM2, which agrees well with the analysis of the inhibitor-residue interactions. Overall, a conclusion can be obtained that the closed conformations of the binding cleft adopted by MDMX is the origin of weaker bindings of inhibitors to MDMX than to MDM2. Studies from Phan and Popowicz et al. also suggested that special conformation of M53 and Y99 leads to a steric clash with inhibitors, which agrees with our current results1977.

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.