Unraveling the Binding Mode of Cyclic Adenosine–Inosine Monophosphate (cAIMP) to STING through Molecular Dynamics Simulations
Meiting Wang,
Baoyi Fan,
Wenfeng Lu,
Ulf Ryde,
Yuxiao Chang,
Di Han,
Jiarui Lu,
Taigang Liu,
Qinghe Gao,
Changpo Chen,
Yongtao Xu
Affiliations
Meiting Wang
School of Medical Engineering & Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang 453003, China
Baoyi Fan
School of Medical Engineering & Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang 453003, China
Wenfeng Lu
School of Medical Engineering & Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang 453003, China
Ulf Ryde
Department of Computational Chemistry, Chemical Centre, Lund University, SE-221 00 Lund, Sweden
Yuxiao Chang
School of Medical Engineering & Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang 453003, China
Di Han
School of Medical Engineering & Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang 453003, China
Jiarui Lu
School of Medical Engineering & Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang 453003, China
Taigang Liu
School of Medical Engineering & Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang 453003, China
Qinghe Gao
School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China
Changpo Chen
Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
Yongtao Xu
School of Medical Engineering & Henan International Joint Laboratory of Neural Information Analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang 453003, China
The stimulator of interferon genes (STING) plays a significant role in immune defense and protection against tumor proliferation. Many cyclic dinucleotide (CDN) analogues have been reported to regulate its activity, but the dynamic process involved when the ligands activate STING remains unclear. In this work, all-atom molecular dynamics simulations were performed to explore the binding mode between human STING (hSTING) and four cyclic adenosine–inosine monophosphate analogs (cAIMPs), as well as 2′,3′-cGMP-AMP (2′,3′-cGAMP). The results indicate that these cAIMPs adopt a U-shaped configuration within the binding pocket, forming extensive non-covalent interaction networks with hSTING. These interactions play a significant role in augmenting the binding, particularly in interactions with Tyr167, Arg238, Thr263, and Thr267. Additionally, the presence of hydrophobic interactions between the ligand and the receptor further contributes to the overall stability of the binding. In this work, the conformational changes in hSTING upon binding these cAIMPs were also studied and a significant tendency for hSTING to shift from open to closed state was observed after binding some of the cAIMP ligands.
