Limits...
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.


Time evolution of the secondary structure profile of MDMX in the pDI6W-MDMX complex: (A) for the polarizable ff02.r1/POL3 combination.(B) for the non-polarizable ff03/TIP3P combination; Anti and Para represent anti-parallel beta-sheet and parallel beta-sheet, respectively, while Pi, 3–10 and Alpha represent Pi (3–14) helix, 3–10 helix and alpha helix.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4663504&req=5

f2: Time evolution of the secondary structure profile of MDMX in the pDI6W-MDMX complex: (A) for the polarizable ff02.r1/POL3 combination.(B) for the non-polarizable ff03/TIP3P combination; Anti and Para represent anti-parallel beta-sheet and parallel beta-sheet, respectively, while Pi, 3–10 and Alpha represent Pi (3–14) helix, 3–10 helix and alpha helix.

Mentions: The combination of the Cpptraj program72 and the DSSP second structure analysis73 was applied to estimate the stability of the second structure of MDM2 and MDMX in two different-type simulations. Figure 2 and Figure S2 describe the time evolution of the secondary structure profiles of MDMX and MDM2 in the polarizable and non-polarizable MD simulations. One can observe that the polarizable ff02.r1/POL3 combination can lead to a slightly more stable second structure relative to the non-polarizable ff03/TIP3P combination. This result agrees well with the earlier reports6574. The time evolution of the number of hydrogen bonds in the complex through simulation is analyzed by using the Cpptraj program and plotted in Figure S3. The results show that the average number of hydrogen bonds in polarizable MD simulations are ~20 more than that in the non-polarizable MD simulations. This result gives a rational reason why the polarizable MD simulations can better stabilize the second structure. Based on the above results, all post-processing analyses are performed on the trajectories of polarizable MD simulations.


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)

Time evolution of the secondary structure profile of MDMX in the pDI6W-MDMX complex: (A) for the polarizable ff02.r1/POL3 combination.(B) for the non-polarizable ff03/TIP3P combination; Anti and Para represent anti-parallel beta-sheet and parallel beta-sheet, respectively, while Pi, 3–10 and Alpha represent Pi (3–14) helix, 3–10 helix and alpha helix.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Time evolution of the secondary structure profile of MDMX in the pDI6W-MDMX complex: (A) for the polarizable ff02.r1/POL3 combination.(B) for the non-polarizable ff03/TIP3P combination; Anti and Para represent anti-parallel beta-sheet and parallel beta-sheet, respectively, while Pi, 3–10 and Alpha represent Pi (3–14) helix, 3–10 helix and alpha helix.
Mentions: The combination of the Cpptraj program72 and the DSSP second structure analysis73 was applied to estimate the stability of the second structure of MDM2 and MDMX in two different-type simulations. Figure 2 and Figure S2 describe the time evolution of the secondary structure profiles of MDMX and MDM2 in the polarizable and non-polarizable MD simulations. One can observe that the polarizable ff02.r1/POL3 combination can lead to a slightly more stable second structure relative to the non-polarizable ff03/TIP3P combination. This result agrees well with the earlier reports6574. The time evolution of the number of hydrogen bonds in the complex through simulation is analyzed by using the Cpptraj program and plotted in Figure S3. The results show that the average number of hydrogen bonds in polarizable MD simulations are ~20 more than that in the non-polarizable MD simulations. This result gives a rational reason why the polarizable MD simulations can better stabilize the second structure. Based on the above results, all post-processing analyses are performed on the trajectories of polarizable MD simulations.

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.