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How do the mutations in PfK13 protein promote anti-malarial drug resistance?

Shikha Sharma1, Md Ehesan Ali1

  • 1Institute of Nano Science and Technology, Sector-81, Mohali, Punjab, India.

Journal of Biomolecular Structure & Dynamics
|September 24, 2022
PubMed

Insights

Plasmodium falciparum Kelch13 (PfK13) mutations linked to artemisinin resistance do not alter protein structure but change protein dynamics. These dynamics may disrupt ubiquitination, causing drug resistance.

Area of Science:

  • Molecular Biology
  • Parasitology
  • Drug Resistance Studies

Background:

  • Artemisinin resistance in Plasmodium falciparum is a growing public health concern.
  • Specific mutations in the Plasmodium falciparum Kelch13 (PfK13) protein are associated with this resistance.
  • The precise molecular mechanisms linking PfK13 mutations to drug resistance remain incompletely understood.

Purpose of the Study:

  • To investigate the impact of PfK13 mutations on protein dynamics.
  • To elucidate the relationship between PfK13 mutation-induced dynamics and the mechanism of artemisinin resistance.

Main Methods:

  • Classical molecular dynamics (MD) simulations were employed to analyze protein dynamics.
  • Trajectory analysis included root-mean-square fluctuations (RMSF), secondary structure prediction, and dynamical cross-correlation matrix (DCCM) analysis.

Main Results:

  • PfK13 mutations (Y493H, R539T, I543T, C580Y) did not cause structural changes at the mutation site.
  • Mutations significantly altered the overall protein dynamics.
  • Enhanced dynamical fluctuations were observed in the BTB-domain loop regions for Y493H and C580Y mutants.

Conclusions:

  • Altered protein dynamics in PfK13 mutants, particularly in the BTB-domain, may affect PfK13-Cullin binding.
  • Disruption of the ubiquitination process due to altered dynamics is a potential mechanism for artemisinin resistance.
  • Further research is needed to fully elucidate the link between PfK13 dynamics and drug resistance.
Keywords:
Molecular dynamic simulationsPfKelch13artemisinin resistancemalaria

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