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Molecular modeling study on the differential microtubule-stabilizing effect in singly- and doubly-bonded complexes

Matías A Zúñiga1, Joel B Alderete2, Gonzalo A Jaña1

  • 1Department of Chemical Sciences, Faculty of Exact Sciencies, Universidad Andres Bello, Sede Concepción, Autopista Concepción-Talcahuano, Talcahuano, Chile.

Proteins
|April 9, 2019
PubMed

Insights

Microtubule stabilizers like peloruside A (PLA) and taxol (TX) affect cell division. Dual binding of PLA and TX to microtubules enhances their stability and structural regularity, crucial for cancer therapy insights.

Area of Science:

  • Cell Biology
  • Biophysics
  • Pharmacology

Background:

  • Microtubules (MTs) are vital cytoskeletal polymers essential for cell division.
  • MT stabilizers are used in cancer therapy to inhibit cell proliferation.
  • Peloruside A (PLA) and taxol (TX) are MT stabilizers with distinct binding sites and effects on MT lattice structure.

Purpose of the Study:

  • To investigate the structural and energetic effects of single and dual binding of PLA and TX on MTs.
  • To understand the molecular mechanisms behind the differential stabilization and regularization effects of PLA and TX.

Main Methods:

  • Fully-atomistic molecular dynamics simulations of reduced MT models.
  • Analysis of structural and energetic changes upon MT stabilizer binding.

Main Results:

  • Dual association of PLA/TX strengthens lateral tubulin dimer contacts compared to single binding.
  • PLA/TX dual binding promotes a more parallel arrangement of tubulin dimers.
  • Increased restriction of interdimeric motion in dual-bound complexes favors 13-protofilament MT structures.

Conclusions:

  • Dual binding of PLA/TX leads to enhanced MT stabilization and regularization.
  • These findings deepen the understanding of MT stabilizer mechanisms.
  • The overstabilization in dual-bound systems offers insights for cancer therapeutic strategies.
Keywords:
microtubule-stabilizing agentsmicrotubulesmolecular dynamicssynergism

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