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Effect of in vivo post-translational modifications of the HMGB1 protein upon binding to platinated DNA: a molecular

Wenping Lyu Lv1,2,3, Fabio Arnesano4, Paolo Carloni1

  • 1Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425 Jülich, Germany.

Nucleic Acids Research
|November 9, 2018
PubMed

Insights

Post-translational modifications (PTMs) on High Mobility Group Box (HMGB) proteins enhance their binding to cisplatin-damaged DNA (PtDNA). This molecular insight could improve anticancer drug efficacy by overcoming cisplatin resistance.

Area of Science:

  • Molecular biology
  • Biochemistry
  • Computational chemistry

Background:

  • Cisplatin is a vital anticancer drug, but its effectiveness is limited by drug resistance.
  • High Mobility Group Box (HMGB) proteins can sensitize tumor cells to cisplatin by binding to platinated DNA (PtDNA).
  • In vivo, the interaction between HMGB proteins and PtDNA is modulated by multisite post-translational modifications (PTMs).

Purpose of the Study:

  • To investigate the impact of PTMs on the HMGB/PtDNA complex at an atomistic level.
  • To understand how PTMs influence the binding affinity and stability of HMGB proteins to PtDNA.

Main Methods:

  • Utilized enhanced sampling molecular simulations to study the HMGB/PtDNA complex.
  • Analyzed the effects of PTMs on the complex's structure, region mobility, and protein/PtDNA non-covalent interactions.

Main Results:

  • PTMs alter the structure and dynamics of the HMGB/PtDNA complex, including the mobility of the platinated DNA site.
  • Multisite PTMs synchronize protein-PtDNA contacts, enhancing the stability of key hydrophobic interactions at the platinated site.
  • The increased stability of these interactions correlates with experimentally observed higher affinity of PTM-modified HMGB proteins for PtDNA.

Conclusions:

  • Multisite PTMs significantly enhance the binding of HMGB proteins to PtDNA by synchronizing intermolecular contacts.
  • This enhanced binding mechanism, driven by PTMs, offers a potential strategy to overcome cisplatin resistance in cancer therapy.
  • The collective behavior of PTMs in modulating intermolecular recognition may have broader implications in biological systems.

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