G12 mutations rewire allosteric communication at the Ras-RalGDS interface.

Area of Science:

• Molecular Biology
• Biochemistry
• Computational Biology

Background:

• The Ras subfamily is crucial in cell signaling, with mutations in RAS genes found in 20% of human tumors.
• The Ras/RalGDS/Ral pathway is increasingly recognized for its role in colon and pancreatic cancer progression.

Purpose of the Study:

• To investigate the molecular interactions between Ras proteins and the Ras binding domain (RBD) of RalGDS.
• To understand how specific Ras mutations influence these interactions and downstream signaling.

Main Methods:

• Long-timescale molecular dynamics (MD) simulations were employed to model Ras-RalGDS interactions.
• Binding free energy calculations and analysis of bonding profiles were used to characterize interactions.

Main Results:

• Rap1-RBD showed the strongest interaction, while M-Ras-RBD exhibited the weakest, aligning with experimental data.
• G12X mutations were found to favor Glu37-mediated stabilization via specific hydrogen bonds and anion-π interactions.
• Allosteric communication pathways were mapped, revealing divergent signaling dynamics between wild-type and mutant Ras.

Conclusions:

• Ras G12X mutations alter Ras-RalGDS binding dynamics and allosteric signaling.
• These findings provide insights into mutant-specific targeting strategies for cancers with Ral pathway overactivity.