Revealing conformational changes of GTP-bound NRAS mutants probed by GaMD and Markov state models.

The RAS family proteins, including NRAS, are key regulators of intracellular signaling, acting as molecular switches that control essential cellular processes including proliferation and survival. Oncogenic NRAS mutations exert distinct effects on protein function. We employed Gaussian accelerated molecular dynamics simulations and Markov state models, complemented by principal component analysis and correlation network analysis, to delineate the comprehensive conformational landscapes of GTP-bound wild-type NRAS and its oncogenic G12D, Q61R, and C118S mutants. Our findings reveal that these mutations significantly alter the structural dynamics of the switch I and switch II domains. The Q61R mutation tends to stabilize the overall NRAS conformation. Furthermore, mutations induce specific changes in the protein's internal communication networks. These insights into the dynamic properties of oncogenic NRAS mutants provide a robust mechanistic foundation for understanding aberrant signaling and guiding the rational design of novel anti-cancer therapeutics.

• Publication year

  2026

• Venue

  Physical Chemistry, Chemical Physics - PCCP

• Publication date

  2026-02-09

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1039/d5cp04245cPMID 41660764
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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