All-Atom Simulations Uncover Structural and Dynamical Properties of STING Proteins in the Membrane System

Recent studies have shown that the stimulator of interferon
gene
(STING) protein plays a central role in the immune system by facilitating
the production of type I interferons in cells. The STING signaling
pathway is also a prominent activator of cancer-killing T cells that
initiate a powerful adaptive immune response. Since biomolecular signaling
pathways are complicated and not easily identified through traditional
experiments, molecular dynamics (MD) has often been used to study
structural and dynamical responses of biological pathways. Here, we
carried out MD simulations for full-length chicken and human STING
(chSTING and hSTING) proteins. Specifically, we investigated ligand-bound
closed (holo) and ligand-unbound open (apo) forms of STING in the
membrane system by comparing their conformational and dynamical differences.
Our research provides clues for understanding the mechanism of the
STING signaling pathway by uncovering detailed insights for the examined
systems: the residues from each chain in the binding pocket are strongly
correlated to one another in the open STING structure compared with
those in the closed STING structure. Ligand-bound closed STING displays
∼174° rotation of the ligand-binding domain (LBD) relative
to the open STING structure. The dynamical analysis of residue Cys148
located in the linker region of hSTING does not support the earlier
hypothesis that Cys148 can form disulfide bonds between adjacent STING
dimers. We also demonstrate that using the full-length proteins is
critical, since the MD simulations of the LBD portion alone cannot
properly describe the global conformational properties of STING.