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Related Experiment Videos

Binding induced folding in p53-MDM2 complex.

Hai-Feng Chen1, Ray Luo

  • 1Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.

Journal of the American Chemical Society
|February 17, 2007
PubMed
Summary
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The p53-MDM2 interaction stabilizes MDM2, with binding and folding being crucial for function. Molecular dynamics simulations reveal distinct unfolding pathways for bound and unbound MDM2, highlighting differences in structural stability.

Area of Science:

  • Molecular Biology
  • Biophysics
  • Computational Biology

Background:

  • The MDM2 N-terminal domain binds p53's transactivation domain, downregulating transcription.
  • p53 binding stabilizes the MDM2 N-terminal domain, indicating a coupling between binding and folding.
  • This interdependence is vital for functional interactions within the p53-MDM2 complex.

Purpose of the Study:

  • To investigate the interdependence of binding and folding in the p53-MDM2 complex.
  • To study the molecular dynamics of bound and unbound MDM2(N) using explicit-solvent simulations.

Main Methods:

  • Explicit-solvent molecular dynamics (MD) simulations.
  • High-temperature MD simulations for kinetic analysis.
  • Free energy landscape and transition state analyses.

Related Experiment Videos

  • Phi-value analysis to predict structural stability.

    • Main Results:

    • Both bound and apo-MDM2(N) unfold via a two-state process.
    • Bound MDM2 unfolds sequentially: p53 unbinding, tertiary unfolding, then secondary structure unfolding.
    • Unfolding pathways differ, with reversed unfolding order of unstable helices and tertiary contacts compared to apo-MDM2.
    • Transition states for bound MDM2 are more native-like and heterogeneous than apo-MDM2.
    • Stable helices are more native-like in both states, with helix II in bound MDM2 being more native-like.

    Conclusions:

    • The study elucidates distinct unfolding mechanisms for MDM2 when bound to p53 versus in its unbound state.
    • Differences in unfolding pathways and transition states underscore the impact of p53 binding on MDM2 structural dynamics.
    • Findings provide insights into the molecular basis of p53-MDM2 interactions and their regulation.