Distinct dynamics and interaction patterns in H- and K-Ras oncogenic P-loop mutants.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Ras proteins are key regulators of cell signaling.
• Oncogenic mutations in Ras proteins contribute to cancer development.
• The structural and dynamical basis for differential Ras isoform and mutant reactivity is not fully understood.

Purpose of the Study:

• To investigate the effects of amino acid variations on the structure and dynamics of wild type and oncogenic H- and K-Ras mutants.
• To elucidate the molecular mechanisms underlying differential Ras isoform and mutant oncogenicity.

Main Methods:

• Utilized microsecond-scale molecular dynamics simulations.
• Analyzed differences in residue interaction networks and dynamics.
• Examined conformational states related to effector interactions.

Main Results:

• Overall protein structures were similar, but dynamics and interaction networks differed significantly.
• Identified distinct residue interaction patterns and sodium ion binding near GTP in G13D mutants.
• H-Ras variants, especially G12V and G13D, exhibited greater flexibility than K-Ras.
• G12V and G13D H-Ras adopted an effector-defective conformation.

Conclusions:

• Ras variant-specific local structural features and GTP interactions influence GTP release and hydrolysis.
• Differences in dynamics, flexibility, and conformational states have implications for Ras signaling, effector binding, and membrane interactions.
• These findings provide insights into the structural basis of Ras oncogenicity.