The stimulator of
interferon genes (
STING)
protein is a cornerstone of the human immune response. Its activation by
cGAMP in the presence of cytosolic
DNA stimulates the production of
type I interferons and inflammatory
cytokines. In the human population, several
STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against
infections. Understanding the molecular mechanisms of these variants opens perspectives for
personalized medicine treatments against diseases such as
viral infections,
cancers, or autoinflammatory diseases. Through microsecond-scale molecular modeling simulations, contact analyses, and machine learning techniques, we reveal the dynamic behavior of four
STING variants (wild type, G230A, R293Q, and G230A/R293Q) and rationalize the variability of efficiency observed experimentally. Our results show that the decrease in
STING activity is linked to a stiffening of key structural elements of the binding cavity together with changes in the interaction patterns within the
protein.