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Updated: Jun 3, 2025

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
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Atomic-level mechanisms of abnormal activation in NRAS oncogenes from two-dimensional free energy landscapes

Zheyao Hu1, Jordi Martí1

  • 1Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B5-209 Northern Campus, Jordi Girona 1-3, 08034 Barcelona, Catalonia, Spain. jordi.marti@upc.edu.

Nanoscale
|January 8, 2025
PubMed

Insights

NRAS-mutant melanoma is aggressive, lacking targeted therapies. This study uses advanced simulations to reveal NRAS mutation mechanisms at the atomic level, paving the way for new drug development.

Area of Science:

  • Molecular Biology
  • Computational Chemistry
  • Oncology

Background:

  • NRAS-mutant melanoma is a lethal cancer with poor survival rates.
  • Limited understanding of NRAS dynamics hinders the development of targeted therapies.
  • NRAS oncogenes are critical drivers in certain cancers.

Purpose of the Study:

  • To explore the local structures and dynamic behavior of NRAS and its mutants.
  • To elucidate the atomic-level mechanisms underlying NRAS Q61 mutations.
  • To identify stable states and transition pathways for NRAS activation.

Main Methods:

  • Utilized microsecond-scale well-tempered metadynamics simulations.
  • Calculated free energy surfaces to map conformational landscapes.
  • Employed atom-atom distances and angles as reaction coordinates.

Main Results:

  • Accurate local structures of NRAS and mutants were determined.
  • Free energy surfaces revealed key local and global minima and transition states.
  • Atomic-level mechanisms of abnormal NRAS activation were unveiled.

Conclusions:

  • This research provides a quantitative analysis of NRAS mutation mechanisms.
  • The findings advance the understanding of NRAS oncogene activation.
  • Offers new opportunities for designing targeted NRAS inhibitors for melanoma treatment.

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