Molecular Dynamics Simulations Reveal the Modulated Mechanism of STING Conformation

Abstract

Stimulator of interferon genes (STING), which is an integral ER-membrane protein, could induce an antiviral state and boost antitumor immunity. Recent experiments reported that different small molecules could modulate the conformation of the STING. However, the mechanism of small molecules modulating the conformation of STING is still unknown. To illustrate the conformational modulated mechanism of STING by small molecules at atomic level, we investigated the interactions between STING and the small molecules: cGAMP and diABZI with molecular dynamics (MD) simulations method. Interestingly, we found that the residues of STING in the binding pocket are more flexible in the monomers of STING than that in the dimer of STING. We also demonstrated that cGAMP and diABZI have a similar binding mode to STING monomers/dimer, and π-π stacking interactions play important roles for the agonists and STING. Our study proposed mechanistic insights into the STING conformation modulated by small molecules and we suggested that the special molecule (e. g. diABZI) could induce the conformational transition of STING from the "open" monomers to the "closed" dimer state. Our research may provide a clue for the development of cancer immunotherapy.

Keywords: Binding site; Modulated mechanism; Molecular dynamics simulation; STING; Small molecule; π–π stacking interaction.