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Unraveling the Binding Mode of Cyclic Adenosine–Inosine Monophosphate (cAIMP) to STING through Molecular Dynamics Simulations

Wang, Meiting LU ; Fan, Baoyi ; Lu, Wenfeng ; Ryde, Ulf LU orcid ; Chang, Yuxiao ; Han, Di ; Lu, Jiarui ; Liu, Taigang ; Gao, Qinghe and Chen, Changpo , et al. (2024) In Molecules 29(11).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
binding mode, cAIMP, conformational change, free energy calculation, molecular dynamics, STING
in
Molecules
volume
29
issue
11
article number
2650
publisher
MDPI AG
external identifiers
  • scopus:85195796928
  • pmid:38893524
ISSN
1420-3049
DOI
10.3390/molecules29112650
language
English
LU publication?
yes
id
8ba3b3d0-0495-4cea-916b-60fcd7945d9b
date added to LUP
2024-08-20 13:20:23
date last changed
2024-08-21 03:00:03
@article{8ba3b3d0-0495-4cea-916b-60fcd7945d9b,
  abstract     = {{<p>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.</p>}},
  author       = {{Wang, Meiting and Fan, Baoyi and Lu, Wenfeng and Ryde, Ulf and Chang, Yuxiao and Han, Di and Lu, Jiarui and Liu, Taigang and Gao, Qinghe and Chen, Changpo and Xu, Yongtao}},
  issn         = {{1420-3049}},
  keywords     = {{binding mode; cAIMP; conformational change; free energy calculation; molecular dynamics; STING}},
  language     = {{eng}},
  number       = {{11}},
  publisher    = {{MDPI AG}},
  series       = {{Molecules}},
  title        = {{Unraveling the Binding Mode of Cyclic Adenosine–Inosine Monophosphate (cAIMP) to STING through Molecular Dynamics Simulations}},
  url          = {{http://dx.doi.org/10.3390/molecules29112650}},
  doi          = {{10.3390/molecules29112650}},
  volume       = {{29}},
  year         = {{2024}},
}