Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation

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.

Designing dual inhibitors of Mdm2/MdmX: Unexpected coupling of water with gatekeeper Y100/99

“…Mdm2 was mostly in an open state, while MdmX was mostly in a closed state [Figs. (b,c) and (c)], consistent with the original crystal structures and simulation studies …”

“…We also focused our attention on Y100/99 because of its well‐documented role in gating p53 binding. Previous computational studies suggested that the open conformation of Mdm2 increases the size of the pocket, allowing deeper p53 binding, while MdmX in the closed conformation causes a shallower binding pocket and pushes p53 “out”, reducing the binding affinity . It is also proposed that MdmX is closed due to residue differences between Mdm2 and MdmX .…”

“…It is also proposed that MdmX is closed due to residue differences between Mdm2 and MdmX . As a consequence of the conformation of Y99 (and other residue differences notably M53), the binding pocket of MdmX was deemed to be more occluded and less energetically favorable for p53 binding than the pocket in Mdm2, with the K d of p53 (17–29) binding to be 440 and 640 nM for Mdm2 and MdmX respectively . Chen et al .…”

“…(c)]. This conformational change has been hypothesized to have significant consequences associated with p53 binding . Collectively, the aforementioned differences sterically hinder the binding of Mdm2‐specific inhibitors to MdmX and although subtle, these variations clearly pose challenges to dual inhibitor design …”

Molecular Mechanism and Energy Basis of Conformational Diversity of Antibody SPE7 Revealed by Molecular Dynamics Simulation and Principal Component Analysis

“…Molecular dynamics (MD) simulations play an important role in successful exploration of protein-ligand interactions and conformational changes of proteins at the atomic level323334353637383940414243. Principal component (PC) analysis44454647, an important method of post-process analysis based on trajectories of MD simulations, shows a big potential in probing internal dynamics of protein motions4849.…”