Structural and energetic insights into cGAS-DNA monomer and oligomer formation: an MD and mM/GBSA study

Upon binding to cytosolic DNA, the cyclic GMP-AMP synthase (cGAS) is activated to catalyze the synthesis of cGAMP, which then activates downstream effectors and induces innate immune responses. The activation of cGAS relies on the formation of cGAS-DNA oligomers and liquid phase condensation, which are sensitive to the length and concentration of DNA. Although significant progresses have been made for the understanding of such a length- and concentration-dependent activation, some structural and energetic details of the cGAS-DNA oligomerization remains elusive. Here, with molecular dynamics simulations, we report the structure of the cGAS-DNA monomer (the cGAS1-DNA1 complex), in which the DNA binds simultaneously to the major parts of two DNA-binding sites as observed in the cGAS-DNA dimer (the cGAS2-DNA2 complex) and its active site is largely immature. Energetic analysis indicates that two cGAS1-DNA1 complexes are just slightly less stable than the cGAS2-DNA2 complex and there exists a significant energy barrier for the formation of the cGAS2-DNA2 complex from two cGAS1-DNA1 complexes, which provides thermodynamic and kinetic explanations for an experimental observation that cGAS-DNA oligomerization is unfavored in low concentration of cGAS and DNA.