Conformational Flexibility of GRB2 as a Key Factor in the Stability and Regulation of Its Interaction with SOS1

The dysregulated activation of the Ras pathway is directly associated with approximately one-third of human cancer cases. The interaction between the adaptor protein GRB2 and the guanine nucleotide exchange factor SOS1 plays a crucial role in this process, serving as a key link in the activation of Ras. This interaction facilitates signal transduction that regulates essential cellular processes such as proliferation, survival, and differentiation and is, therefore, a central point in oncogenesis. Although the GRB2-SOS1 complex is critical for the regulation of Ras pathway signaling, the structural mechanisms governing this interaction remain largely unknown. In this study, we conducted an in-depth analysis of the interaction between GRB2 and peptides derived from SOS1, utilizing computational modeling, docking, and molecular dynamics simulations, combined with a detailed analysis of the energy landscape (ELViM). The results demonstrate that the conformational flexibility of the GRB2 protein has a direct impact on the stability of the GRB2-SOS1 complex, with communication between GRB2 domains being a determining factor for the robustness of this interaction. Additionally, we identified critical residues that play decisive roles in the formation and regulation of this interaction, which may serve as potential targets for modulation of the Ras pathway. These findings not only deepen the understanding of the structural mechanisms underlying the GRB2-SOS1 interaction but also provide a foundation for the development of specific therapeutic strategies aimed at controlling aberrant Ras pathway signaling, thereby offering new prospects in the treatment of diseases associated with the anomalous activation of Ras.