Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein

Human stimulator of interferon genes (<i>h</i>STING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3′-3′, 2′-2′ or mixed 2′-3′-linkages) and exhibit different binding affinity towards <i>h</i>STING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with <i>h</i>STING<i>^wt</i> protein. Our results revealed that CDN/<i>h</i>STING<i>^wt</i> interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in <i>h</i>STING<i>^wt</i> ligand binding cavity, especially in α₁-helices, the so-called lid region and α₂-tails. The ligand residence time in <i>h</i>STING<i>^wt</i> protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of <i>h</i>STING<i>^wt</i> protein. These findings may perhaps guide design of new compounds modulating <i>h</i>STING activity. Communicated by Ramaswamy H. Sarma