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Updated: Sep 17, 2025

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A Full-Scaled Perspective of K-Ras4B Transformations Modulated by Oncogenic G12D and Phosphorylation in

Yanjiao Wang1, Yi Zhang1, Hao Chen1

  • 1Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Health Science & Biomedical Engineering, Hebei University of Technology, Tianjin 300401, China.

Journal of Chemical Information and Modeling
|June 27, 2025
PubMed

Insights

K-Ras4B mutations like G12D and S181 phosphorylation alter its membrane binding and conformation. These changes influence K-Ras4B

Area of Science:

  • Molecular biology
  • Biophysics
  • Computational chemistry

Background:

  • K-Ras4B is a key oncogenic GTPase involved in cell signaling.
  • Its membrane association and conformation are critical for its function and drug targeting.
  • Mutations and post-translational modifications significantly impact K-Ras4B behavior.

Purpose of the Study:

  • To investigate the effects of G12D mutation and S181 phosphorylation on K-Ras4B membrane association and conformation.
  • To explore the role of lipid raft environments in modulating K-Ras4B states.
  • To elucidate the allosteric mechanisms governing K-Ras4B conformational changes.

Main Methods:

  • All-atom and coarse-grained molecular dynamic simulations.
  • Utilizing phase-segregated lipid bilayers to mimic cellular membrane environments.
  • Employing membrane-less models to isolate effects of mutations.

Main Results:

  • S181 phosphorylation (S181P) drives K-Ras4B to lipid rafts, favoring an inactive (S2) conformation.
  • The G12D mutation promotes an active (S1) conformation by exposing the Switch-I region prior to membrane binding.
  • Local electrostatic repulsion in the G12D mutant enhances Switch-I flexibility and accessibility.

Conclusions:

  • K-Ras4B conformational switching is modulated by both intramolecular allostery and intermolecular membrane interactions.
  • Understanding these mechanisms is crucial for developing novel anticancer drugs targeting K-Ras4B.
  • The study provides multiscaled dynamic perspectives on K-Ras4B signaling and its regulation.

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