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 STING(AQ) 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 STING(AQ) 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 smaller number of water molecules are displaced upon DMXAA binding to STINGAQ than that on binding to its mutants, leading to a larger entropic penalty for the former. Considering the sensitivity of STINGAQ and two of its mutants to DMXAA, a strong structural correlation appears to discourage DMXAA STING binding. Such an observation suggests that DMXAA derivatives, which are deprived of hydrogen-bond interaction with both 162S* and 267T, are potential agonists of human STING.