The stimulator of interferon gene (STING) protein, a signaling molecule, has become a recent focal point in immunological research and future drug discovery for its potential to enhance the ability to kill and fight infection greatly. Recognition of aberrant DNA species or cyclic dinucleotides (CDNs) in the cytosol activates Cyclic GMP-AMP synthase (cGAS) to produce a second messenger ligand, cGAMP, which binds and activates STING. This cGAS-STING signaling pathway triggers multiple signaling cascades leading to the production of Type I interferons. Since structural and dynamics effects through the biomolecular signaling pathways are complicated and not easily identified through traditional experiments, molecular dynamics (MD) has been used to study the dynamics and conformational changes that occur in protein structures.<br/><br/>This study carried out MD simulations for full-length chicken and human STING (chSTING and hSTING) proteins in the membrane environment to study structural deviations from the crystal structures published in Protein Data Bank. We looked at ligand-bound (holo - activated state) closed-form and ligand-unbound (apo – inactive state) open form in the membrane systems. We explored the dynamical differences between apo and holo states and the differences between chicken and human ligand binding sites in STING. Furthermore, the previous study suggested that the uncrossing of the linker region in hSTING increases the availability of cysteine residues to form disulfide bonds between neighboring hSTING dimers for polymer stabilization. So, we investigated the accessibility of cysteine residue 148 (Cys148) located in the linker regions of hSTING to explore its possibility in participation in polymer crosslinking. We believe that the information gathered from our study will add to our overall understanding of the conformational effects induced by ligand binding in a membrane environment and provide further insight into the STING signaling pathway.

Computational studies of full-length chicken and human stimulator of the interferon gene (STING) proteins in membrane systems

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.