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Hidden electrostatic energy contributions define dynamic allosteric communications within p53 during molecular

Sayan Bhattacharjee1, Jayati Sengupta2

  • 1Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India.

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|September 3, 2021
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The tumor suppressor p53 switches between DNA and repressor protein binding via an electrostatic pathway. iASPP binding to p53 alters its electrostatic network, impeding DNA binding and regulating transcription.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Transcription regulation relies on molecular recognition by factors like p53.
  • p53 (tumor suppressor) binds DNA or repressor proteins (e.g., iASPP).
  • The mechanism of p53's conformational switch between DNA and repressor binding is unclear.

Purpose of the Study:

  • Investigate the molecular mechanism of p53 conformational changes.
  • Elucidate nonbonded energy contributions in p53 recognition of DNA and iASPP.
  • Identify the allosteric pathway linking iASPP binding to reduced p53-DNA affinity.

Main Methods:

  • Molecular dynamics simulations of p53 DNA binding domain (p53DBD) with DNA and iASPP.
  • Rigorous analysis of nonbonded energy terms, focusing on electrostatics.
  • Electrostatic network analysis to identify communication pathways and energy hubs.

Main Results:

  • iASPP binding to p53DBD induces an allosteric conformational change.
  • A conserved electrostatic pathway (K120 to R213) mediates allosteric communication.
  • Conformational change in K120 rewires the electrostatic network, impeding DNA binding.
  • Shifting hydrogen bonds and salt bridges alter electrostatic energies within p53DBD.

Conclusions:

  • p53 utilizes a common residue framework but distinct electrostatic interactions for DNA and iASPP binding.
  • iASPP binding allosterically inhibits p53-DNA interaction through electrostatic network rewiring.
  • Understanding this mechanism provides insights into transcription regulation by p53.