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.
Highlights
The tumor suppressor protein p53 plays a key role in maintaining genetic integrity and preventing tumor development[1]
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
Quantum mechanics method was adopted by Ding et al to calculate residue-specific interactions in the p53-MDM2 complex and the results proved that van der Waals interactions drive the p53-MDM2 binding[46], which was supported by previous calculated studies of other groups[47,48,49]
Summary
Difference of inhibitors to MDM2 received: 05 March 2015 accepted: October 2015 Published: November 2015 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation. Non-peptide inhibitors nutlins[20], isoindolinone[21], spiro-oxindoles (MI-63)[22,23] and benzodiazepinedions derivatives[24], have been developed by mimicking the p53-MDM2 interaction These compounds have high binding affinities to MDM2, they cannot efficiently inhibit the p53-MDMX interaction. Due to great success of molecular simulations and predictions of binding free energies in insight into the inhibitor-protein interactions, conformation changes and structure-affinity relationship of proteins[27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45], these methods were applied to study interaction mechanism of inhibitors with MDM2 and MDMX. We expect that this study can contribute an important theoretical guidance and dynamic information for development of potent dual inhibitors blocking the p53-MDM2/MDMX interactions
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