MOLECULAR DYNAMICS AND STRUCTURAL ANALYSIS OF GRB2 AND SOS1 PEPTIDE INTERACTIONS REVEALING CONFORMATIONAL CHANGES

Growth Factor Receptor-Bound Protein 2 (GRB2) is an adaptor protein that plays a pivotal role in the cellular signaling pathway by mediating interactions between activated receptor tyrosine kinases and downstream signaling proteins. GRB2 contains an SH2 domain that specifically recognizes phosphorylated tyrosine residues on these receptors. Additionally, GRB2 interacts with SOS1 through its SH3 domains, termed NSH3 and CSH3. The primary function of SOS1 is to activate the Ras protein, which acts as a molecular switch essential for initiating critical events in intracellular signaling. The interaction between GRB2 and SOS1 is fundamental to the activation of the receptor tyrosine kinase signaling pathway, which regulates cellular processes such as growth, differentiation, and survival. Dysregulation of this pathway can lead to various pathologies, including cancer. Thus, this study aimed to investigate the interaction mechanism between GRB2 and peptides derived from SOS1, particularly those from proline-rich regions, to understand the underlying binding mechanism. To analyze the dynamics of these interactions, we performed molecular dynamics simulations using the Amber99SB-ILDN force field in GROMACS version 2020.3. The simulations included both isolated SH3 domains and the full monomeric protein in two distinct conformations. We selected five peptides from SOS1, originating from potential interaction regions with the SH3 domains, to characterize the interaction between the two proteins. Our results indicate that the NSH3 domain of GRB2 establishes robust interactions with SOS1 peptides S04, S05, and S09, while the CSH3 domain demonstrates higher affinity for peptides S04 and S10. We proposed four interaction models with the complete GRB2 based on literature and observed that the interaction with peptide S04 in the CSH3 domain is the most favorable. We concluded that NSH3 has four equally favorable binding sites, whereas CSH3 presents two alternative binding sites. The interactions between the domains and the peptides occur in distinct manners. Our findings support the hypothesis that NSH3-S05/CSH3-S04 or NSH3-S09/CSH3-S04 interaction models are the most probable, providing greater stability to the GRB2/SOS1 complex.