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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.


Structures of MDM2, MDMX and inhibitors: (A) superimposed structures of MDM2 and MDMX in a cartoon mode, MDM2 is shown in orange and MDMX in violetpurple; (B) structure for pDI6W and (C) structure for pDIQ.
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f1: Structures of MDM2, MDMX and inhibitors: (A) superimposed structures of MDM2 and MDMX in a cartoon mode, MDM2 is shown in orange and MDMX in violetpurple; (B) structure for pDI6W and (C) structure for pDIQ.

Mentions: Recent studies showed that sequence identity in the N-terminal domain of MDM2 and MDMX reaches ~54%, and these two oncoproteins share highly similar overall structure (Fig. 1A)101112. Both MDM2 and MDMX can produce direct interactions with the residues F19′, W23′ and L26′, located in the TA domain of p53, which contribute a majority of binding free energies of p53 to MDM2/MDMX413141516. Up to now, many chemical compounds, such as peptide inhibitors PMI17, P418, pDI6W19 etc. and non-peptide inhibitors nutlins20, isoindolinone21, spiro-oxindoles (MI-63)2223 and benzodiazepinedions derivatives24, have been developed by mimicking the p53-MDM2 interaction. Although these compounds have high binding affinities to MDM2, they cannot efficiently inhibit the p53-MDMX interaction. Moreover, inhibitor bindings can induce large conformational changes of MDM2 and MDMX2526, especially for MDMX, which plays a significant role in clarification of the structure-affinity relationship for the inhibitor-MDM2/MDMX complex. Thus, it is significant to probe origin of the differences in binding modes and conformational changes induced by inhibitor bindings at an atomic level for designs of potent dual inhibitors targeting the p53-MDM2/MDMX interactions.


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)

Structures of MDM2, MDMX and inhibitors: (A) superimposed structures of MDM2 and MDMX in a cartoon mode, MDM2 is shown in orange and MDMX in violetpurple; (B) structure for pDI6W and (C) structure for pDIQ.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Structures of MDM2, MDMX and inhibitors: (A) superimposed structures of MDM2 and MDMX in a cartoon mode, MDM2 is shown in orange and MDMX in violetpurple; (B) structure for pDI6W and (C) structure for pDIQ.
Mentions: Recent studies showed that sequence identity in the N-terminal domain of MDM2 and MDMX reaches ~54%, and these two oncoproteins share highly similar overall structure (Fig. 1A)101112. Both MDM2 and MDMX can produce direct interactions with the residues F19′, W23′ and L26′, located in the TA domain of p53, which contribute a majority of binding free energies of p53 to MDM2/MDMX413141516. Up to now, many chemical compounds, such as peptide inhibitors PMI17, P418, pDI6W19 etc. and non-peptide inhibitors nutlins20, isoindolinone21, spiro-oxindoles (MI-63)2223 and benzodiazepinedions derivatives24, have been developed by mimicking the p53-MDM2 interaction. Although these compounds have high binding affinities to MDM2, they cannot efficiently inhibit the p53-MDMX interaction. Moreover, inhibitor bindings can induce large conformational changes of MDM2 and MDMX2526, especially for MDMX, which plays a significant role in clarification of the structure-affinity relationship for the inhibitor-MDM2/MDMX complex. Thus, it is significant to probe origin of the differences in binding modes and conformational changes induced by inhibitor bindings at an atomic level for designs of potent dual inhibitors targeting the p53-MDM2/MDMX interactions.

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.