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Molecular Dynamics Simulations Reveal the Modulated Mechanism of STING Conformation

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Abstract

Stimulator of interferon genes (STING), which is an integral ER-membrane protein, could induce an antiviral state and boost antitumor immunity. Recent experiments reported that different small molecules could modulate the conformation of the STING. However, the mechanism of small molecules modulating the conformation of STING is still unknown. To illustrate the conformational modulated mechanism of STING by small molecules at atomic level, we investigated the interactions between STING and the small molecules: cGAMP and diABZI with molecular dynamics (MD) simulations method. Interestingly, we found that the residues of STING in the binding pocket are more flexible in the monomers of STING than that in the dimer of STING. We also demonstrated that cGAMP and diABZI have a similar binding mode to STING monomers/dimer, and π–π stacking interactions play important roles for the agonists and STING. Our study proposed mechanistic insights into the STING conformation modulated by small molecules and we suggested that the special molecule (e. g. diABZI) could induce the conformational transition of STING from the “open” monomers to the “closed” dimer state. Our research may provide a clue for the development of cancer immunotherapy.

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Acknowledgements

Qingjie Zhao thanks the supporting from the "Personalized Medicines–Molecular Signature–based Drug Discovery and Development".

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Authors and Affiliations

  1. College of Mathematics and Physics, Shanghai University of Electric Power, Shanghai, 200090, China

    Li Chen, Shuang Zhao, Yanyan Zhu, Yongsheng Liu & Huiyu Li

  2. Shanghai Institute of Material Medical, Chinese Academy of Sciences, Shanghai, 201203, China

    Qingjie Zhao

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  1. Li Chen
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Contributions

LC, HL and QZ conceived and designed the research. LC performed the simulations. LC, SZ, YZ and YL analysed the simulation data. LC and HL wrote the paper. The article was approved by all authors.

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Correspondence to Huiyu Li or Qingjie Zhao.

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Chen, L., Zhao, S., Zhu, Y. et al. Molecular Dynamics Simulations Reveal the Modulated Mechanism of STING Conformation. Interdiscip Sci Comput Life Sci 13, 751–765 (2021). https://doi.org/10.1007/s12539-021-00446-3

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