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Computational insights on the molecular interplay between KRas (G12D mutation) and SOS1 modulated by the inhibitor

Juan Zeng1, YiXuan Lan1, Fei Xia2,3

  • 1School of Biomedical Engineering, Guangdong Medical University, Dongguan, China.

Plos Computational Biology
|April 29, 2026
PubMed

Insights

Mutations in KRas proteins drive cancer by altering interactions with Son of Sevenless (SOS). The G12D mutation and BI-3406 inhibitor impact KRas-SOS binding, offering new therapeutic strategies for KRas-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ras proteins, particularly KRas, are key oncogenes implicated in ~80% of cancers with Ras mutations.
  • The precise mechanisms linking Ras mutations to oncogenesis remain incompletely understood.
  • Human Son of Sevenless (SOS) facilitates Ras guanine nucleotide exchange, a critical step in Ras-mediated signaling and cancer development.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying KRas-SOS interactions, focusing on the impact of the KRas G12D mutation and the SOS1 inhibitor BI-3406.
  • To investigate how these factors modulate binding affinities and affect the KRas-SOS complex formation.
  • To provide insights for the rational design of novel co-targeting inhibitors against KRas-mutated cancers.

Main Methods:

  • Construction of a functional ternary complex: (KRasGDP·Mg2+)·SOS1·(KRasGTP·Mg2+).
  • Molecular dynamics (MD) simulations to analyze KRas-SOS interactions under different conditions (G12D mutation, BI-3406 treatment).
  • Assessment of changes in binding affinities and interfacial electrostatic landscapes.

Main Results:

  • Both the KRas G12D mutation and the SOS1 inhibitor BI-3406 significantly affect KRas-SOS interactions, primarily through the Switch-II (SW2) region of KRas.
  • The G12D mutation, featuring a negatively charged Asp12, alters electrostatic landscapes and reduces binding affinities by ~25 kcal/mol for both KRasGDP·Mg2+ and KRasGTP·Mg2+.
  • BI-3406 disrupts WT KRas-SOS interactions by forming a hydrogen bond bridge involving SW2, while it differentially affects the binding of GDP-bound and GTP-bound KRas, enhancing G12D-mutant KRasGTP·Mg2+ binding.

Conclusions:

  • The study reveals specific molecular mechanisms by which the G12D mutation and BI-3406 modulate KRas-SOS interactions.
  • BI-3406's differential effects on KRasGDP and KRasGTP binding, particularly its enhancement of G12D-mutant KRasGTP binding, promote SOS1's preference for KRasGTP and inhibit G12D-KRas-driven tumor growth.
  • These findings offer valuable mechanistic insights for developing potent SOS1-co-targeting inhibitors to enhance antitumor efficacy in G12D-mutated KRas cancers.

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