Functional diversity in G-protein signalling: In-silico study of G-protein γ subunit induced behavioural alteration in G-protein β subunit hotspot.

The components of G protein signalling in higher eukaryotes consist of G-Protein Coupled Receptors and heterotrimeric G-protein complexes (Gαβγ). In humans, there are five variants of the Gβ subunit and twelve variants of the Gγ subunit. They can form up to 60 distinct Gβγ complexes. Each complex is known to have a different signalling pathway. The Gγ subunit is recognised for its role in determining the effector specificity of the Gβγ complex. To understand the role of the Gγ subunit in determining the effector specificity of the Gβγ complex, the interaction of Gγ with various interacting partners was analysed. Molecular dynamics simulations were performed on 12 possible Gβ1γ complexes, and the available PDB structures of the Gαi1-Gβ1γ1 (5KDO) and Gαi1-Gβ1γ2 (1GP2) complexes. The analysis demonstrated that the interaction of the Gγ subunit with Gα and the GPCR subunit is possible. It was found that each Gγ subunit can interact with the Gβ subunit in a distinct binding mode, thereby allosterically modulating the Gβ subunit's hotspot residues. Our MD simulation studies also indicate that the Gαi1 subunit has a high affinity for Gβ1γ1 over Gβ1γ2 to form the heterotrimeric Gαβγ complex. In conclusion, binding of Gγ subunits allosterically modulates the flexibility and accessibility of the Gβ hotspot residues in the Gβγ complex, potentially influencing interactions between the Gβγ and its interacting partners.