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Differential binding of p53 and nutlin to MDM2 and MDMX: computational studies
Thomas Leonard Joseph1, Arumugam Madhumalar, Christopher J Brown
1Bioinformatics Institute (A-STAR), Matrix, Singapore.
Abstract:
Half of human tumours have mutated p53 while in the other half, defective signalling pathways block its function. One such defect is the overexpression of the MDM2 and MDMX proteins. This has led to an intense effort to develop inhibitors of p53-MDM2/MDMX interactions. Nutlin is the first such compound described to block p53-MDM2 interactions. Molecular dynamics simulations have been used to explore the differences in binding of p53 and nutlin to MDM2/MDMX. Simulations reveal that p53 has a higher affinity for MDM2 than MDMX, driven by stronger electrostatic interactions. p53 is displaced from MDM2 by nutlin because it is more flexible, thus paying a larger entropic penalty upon sequestration by MDM2. The inherent plasticity of MDM2 is higher than that of MDMX, enabling it to bind both p53 and nutlin. The less flexible MDMX interacts with the more mobile p53 because the peptide can adapt conformationally to dock into MDMX, albeit with a reduced affinity; nutlin, however is rigid and hence can only interact with MDMX with low affinity. Evolutionarily, the higher affinity of MDM2 for p53 may enable MDM2 to bind p53 for longer periods as it shuttles it out of the nucleus; in contrast, MDMX only needs to mask the p53 TA domain. This study enables us to hypothesize gain of function mutations or those that have decreased affinity for nutlin. These conclusions provide insight into future drug design for dual inhibitors of MDM2 and MDMX, both of which are oncoproteins found overexpressed in many cancers.
Insights
Tumor suppressor p53 function is often lost in cancer due to mutations or overexpression of MDM2 and MDMX proteins. Molecular dynamics reveal p53 binds MDM2 stronger than MDMX, and Nutlin drug displaces p53 from MDM2.
Area of Science:
- Oncology
- Molecular Biology
- Biophysics
Background:
- Half of human tumors exhibit p53 mutations; the other half have impaired p53 signaling.
- Overexpression of MDM2 and MDMX proteins is a common defect, inhibiting p53 function.
- Developing inhibitors of p53-MDM2/MDMX interactions is a key cancer therapeutic strategy.
Purpose of the Study:
- To explore differences in binding affinities and mechanisms between p53, Nutlin, MDM2, and MDMX using molecular dynamics simulations.
- To understand the structural and dynamic basis for p53 and Nutlin interactions with MDM2 and MDMX.
- To provide insights for designing dual inhibitors targeting MDM2 and MDMX.
Main Methods:
- Molecular dynamics simulations were employed to analyze the interactions of p53 and Nutlin with MDM2 and MDMX.
- Binding affinities and conformational dynamics were assessed through computational modeling.
Main Results:
- p53 exhibits higher binding affinity for MDM2 than MDMX, primarily due to stronger electrostatic interactions.
- Nutlin displaces p53 from MDM2 due to p53's flexibility and the entropic penalty of binding.
- MDM2 demonstrates higher plasticity than MDMX, allowing it to bind both p53 and Nutlin.
Conclusions:
- MDM2's higher affinity for p53 may facilitate prolonged nuclear export, while MDMX primarily masks the p53 transactivation domain.
- The study suggests potential gain-of-function mutations or decreased Nutlin affinity.
- Findings offer crucial insights for the future design of dual MDM2/MDMX inhibitors for cancer therapy.
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