Structural and Energetic Details for the Formation of cGAS-DNA Oligomers

Abstract 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. For a thorough understanding of such a length-and concentration-dependent activation, the details of the cGAS-DNA oligomerization are required. Here, with molecular dynamics (MD) simulations, we report the structure of the cGAS-DNA monomer (the cGAS 1 -DNA 1 complex), in which the DNA binds simultaneously to the major parts of two DNA-binding sites as observed in the cGAS-DNA dimer (the cGAS 2 -DNA 2 complex) and the active site is largely immature. Energetic analysis reveals that two cGAS 1 -DNA 1 complexes are just slightly less stable than the cGAS 2 -DNA 2 complex and the energy barrier for the formation of cGAS 2 -DNA 2 complex from two cGAS 1 -DNA 1 complexes is high, suggesting that cGAS-DNA oligomerization is unfavored thermodynamically and kinetically in low concentration of cGAS and DNA. However, the formation of cGAS 4 -DNA 2 complex from one molecule of cGAS 2 -DNA 2 complex between cGAS and long DNA and two molecules of cGAS are energetically favored without energy barrier.