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

Abstract

Human stimulator of interferon genes (hSTING) 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 hSTING, 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 hSTING^wt protein. Our results revealed that CDN/hSTING^wt 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 hSTING^wt ligand binding cavity, especially in α₁-helices, the so-called lid region and α₂-tails. The ligand residence time in hSTING^wt 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 hSTING^wt protein. These findings may perhaps guide design of new compounds modulating hSTING activity.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human stimulator of interferon genes STING
• cyclic dinucleotides CDNs
• Molecular Dynamics

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Czech Academy of Sciences (RVO 86652036) and by projects ELIXIR-CZ: Building The Capacity (CZ.02.1.01/0.0/0.0/16_013/0001777) and BIOCEV (CZ.1.05/1.1.00/02.0109) from the ERDF and MEYS Czech Republic and by projects ELIXIR CZ (LM2018131) and CIISB4HEALTH (CZ.02.1.01/0.0/0.0/16_013/0001776) from MEYS Czech Republic. The financial support of the Grant Agency of the Czech Republic is also gratefully acknowledged (grant 20-08772S). Computational resources were supplied by the project "e-Infrastruktura CZ" (e-INFRA LM2018140) and IT4I supercomputer center (LM2015070), provided within the program Projects of Large Research, Development and Innovations Infrastructures.