pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations
Abstract The pH‐dependent assembly of Toll‐like receptors (TLRs), which triggers a threshold‐like response, is a key principle in immune signaling. While crystallography has revealed the intricate structure of these assembly complexes, the mechanisms underlying their pH dependency remain unclear. He...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202411445 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841553166106099712 |
|---|---|
| author | Penghui Li Mingsong Shi Yibo Wang Qiong Liu Xiubo Du Xiaohui Wang |
| author_facet | Penghui Li Mingsong Shi Yibo Wang Qiong Liu Xiubo Du Xiaohui Wang |
| author_sort | Penghui Li |
| collection | DOAJ |
| description | Abstract The pH‐dependent assembly of Toll‐like receptors (TLRs), which triggers a threshold‐like response, is a key principle in immune signaling. While crystallography has revealed the intricate structure of these assembly complexes, the mechanisms underlying their pH dependency remain unclear. Herein, constant pH simulations and metadynamics are employed to investigate the pH‐dependent assembly and stability of the TLR3/dsRNA signaling complex. The findings demonstrate that system pH regulates complex assembly and stability by modulating the protonation and charge states of histidines. Histidines in TLR3 act as pH‐dependent, positively charged binding sites that capture negatively charged dsRNA. Additionally, these histidines form a [H682⁺]—[E626⁻] dipole, facilitating the assembly of two TLR3 molecules into an antisymmetric dimer through dipole–dipole interactions. Surprisingly, TLR3 can shift the pKa values of key histidines from their model pKa of 6.5, increasing protonation likelihood and enhancing ligand binding. Notably, the aromatic residue Phe84, located within the dsRNA binding site [His39⁺–His60⁺–Phe84–His108⁺], alters the pKa of His60 through cation‐π interactions with its protonated state. This study offers new insights into the molecular mechanisms underlying pH‐dependent immune signaling via higher‐order assemblies and suggests potential applications for histidine in self‐assembling biomaterials. |
| format | Article |
| id | doaj-art-999ba5ffac174ac2940790ff2a9c7d50 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-999ba5ffac174ac2940790ff2a9c7d502025-01-09T11:44:46ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202411445pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics SimulationsPenghui Li0Mingsong Shi1Yibo Wang2Qiong Liu3Xiubo Du4Xiaohui Wang5Shenzhen Key Laboratory of Marine Biotechnology and Ecology College of Life Sciences & Oceanography Shenzhen University Shenzhen 518055 ChinaNHC Key Laboratory of Nuclear Technology Medical Transformation Mianyang Central Hospital School of Medicine University of Electronic Science and Technology of China Mianyang Sichuan 621099 ChinaLaboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaShenzhen Key Laboratory of Marine Biotechnology and Ecology College of Life Sciences & Oceanography Shenzhen University Shenzhen 518055 ChinaShenzhen Key Laboratory of Marine Biotechnology and Ecology College of Life Sciences & Oceanography Shenzhen University Shenzhen 518055 ChinaLaboratory of Chemical Biology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaAbstract The pH‐dependent assembly of Toll‐like receptors (TLRs), which triggers a threshold‐like response, is a key principle in immune signaling. While crystallography has revealed the intricate structure of these assembly complexes, the mechanisms underlying their pH dependency remain unclear. Herein, constant pH simulations and metadynamics are employed to investigate the pH‐dependent assembly and stability of the TLR3/dsRNA signaling complex. The findings demonstrate that system pH regulates complex assembly and stability by modulating the protonation and charge states of histidines. Histidines in TLR3 act as pH‐dependent, positively charged binding sites that capture negatively charged dsRNA. Additionally, these histidines form a [H682⁺]—[E626⁻] dipole, facilitating the assembly of two TLR3 molecules into an antisymmetric dimer through dipole–dipole interactions. Surprisingly, TLR3 can shift the pKa values of key histidines from their model pKa of 6.5, increasing protonation likelihood and enhancing ligand binding. Notably, the aromatic residue Phe84, located within the dsRNA binding site [His39⁺–His60⁺–Phe84–His108⁺], alters the pKa of His60 through cation‐π interactions with its protonated state. This study offers new insights into the molecular mechanisms underlying pH‐dependent immune signaling via higher‐order assemblies and suggests potential applications for histidine in self‐assembling biomaterials.https://doi.org/10.1002/advs.202411445cation‐π Interactiondouble strand RNAmolecular dynamics simulationsmolecular recognitionToll‐like receptor 3 (TLR3) |
| spellingShingle | Penghui Li Mingsong Shi Yibo Wang Qiong Liu Xiubo Du Xiaohui Wang pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations Advanced Science cation‐π Interaction double strand RNA molecular dynamics simulations molecular recognition Toll‐like receptor 3 (TLR3) |
| title | pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations |
| title_full | pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations |
| title_fullStr | pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations |
| title_full_unstemmed | pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations |
| title_short | pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations |
| title_sort | ph dependent assembly and stability of toll like receptor 3 dsrna signaling complex insights from constant ph molecular dynamics and metadynamics simulations |
| topic | cation‐π Interaction double strand RNA molecular dynamics simulations molecular recognition Toll‐like receptor 3 (TLR3) |
| url | https://doi.org/10.1002/advs.202411445 |
| work_keys_str_mv | AT penghuili phdependentassemblyandstabilityoftolllikereceptor3dsrnasignalingcomplexinsightsfromconstantphmoleculardynamicsandmetadynamicssimulations AT mingsongshi phdependentassemblyandstabilityoftolllikereceptor3dsrnasignalingcomplexinsightsfromconstantphmoleculardynamicsandmetadynamicssimulations AT yibowang phdependentassemblyandstabilityoftolllikereceptor3dsrnasignalingcomplexinsightsfromconstantphmoleculardynamicsandmetadynamicssimulations AT qiongliu phdependentassemblyandstabilityoftolllikereceptor3dsrnasignalingcomplexinsightsfromconstantphmoleculardynamicsandmetadynamicssimulations AT xiubodu phdependentassemblyandstabilityoftolllikereceptor3dsrnasignalingcomplexinsightsfromconstantphmoleculardynamicsandmetadynamicssimulations AT xiaohuiwang phdependentassemblyandstabilityoftolllikereceptor3dsrnasignalingcomplexinsightsfromconstantphmoleculardynamicsandmetadynamicssimulations |