Single Mutations Reshape the Structural Correlation Network of the DMXAA–Human STING Complex

Subtle changes in protein sequences are able to alter ligand–protein interactions. Unraveling the mechanism of such phenomena is important for understanding ligand–protein interactions, including the DMXAA–STING interaction. DMXAA specifically binds to mouse STING instead of human STING. However, the S162A mutation and a newly discovered E260I mutation endow human STINGAQ with DMXAA sensitivity. Through molecular dynamics simulations, we revealed how these single mutations alter the DMXAA–STING interaction. Compared to mutated systems, structural correlations in the interaction of STINGAQ with DMXAA are stronger, and the correlations are cross-protomers in the dimeric protein. Analyses on correlation coefficients lead to the identification of two key interactions that mediate the strong cross-protomer correlation in the DMXAA–STINGAQ interaction network: DMXAA–267T–162S* and 238R–260E*. These two interactions are partially and totally interrupted by the S162A and E260I mutations, respectively. Moreover, a...