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Molecular dynamic simulation reveals damaging impact of RAC1 F28L mutation in the switch I region

Ambuj Kumar1, Vidya Rajendran, Rao Sethumadhavan

  • 1Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology University, Vellore, Tamil Nadu, India.

Plos One
|October 23, 2013
PubMed

Insights

The RAC1 F28L mutation, linked to cancer, causes significant conformational changes in the Switch I region. This structural alteration disrupts guanine binding, potentially explaining its oncogenic transformation and role in cancer.

Area of Science:

  • Molecular biology
  • Biochemistry
  • Computational biology

Background:

  • Ras-related C3 botulinum toxin substrate 1 (RAC1) is a small GTPase involved in cancer-associated phenotypes.
  • The RAC1 F28L mutation is a fast-recycling variant implicated in various cancers.

Purpose of the Study:

  • To investigate the conformational changes in the RAC1 F28L mutant protein.
  • To understand the molecular mechanisms underlying the oncogenic potential of the RAC1 F28L mutation.

Main Methods:

  • Molecular docking simulations.
  • Molecular dynamics simulations (~0.3 μs).
  • Analysis of RMSD, RMSF, and NHbonds.

Main Results:

  • The RAC1 F28L mutation induces significant conformational changes, particularly in the Switch I region.
  • The mutant protein adopts a more compact conformation compared to the native form.
  • Loss of native conformation in Switch I may disrupt guanine ring interaction due to F28 residue.

Conclusions:

  • The conformational instability in the Switch I region of the RAC1 F28L mutant is a key factor in its oncogenic transformation.
  • Altered protein conformation affects guanine binding, contributing to cancer-associated phenotypes.

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