tetano
Editor, Senior Moderator
Front Microbiol
. 2021 Dec 1;12:789062.
doi: 10.3389/fmicb.2021.789062. eCollection 2021.
Structural Analysis on the Severe Acute Respiratory Syndrome Coronavirus 2 Non-structural Protein 13 Mutants Revealed Altered Bonding Network With TANK Binding Kinase 1 to Evade Host Immune System
Farooq Rashid[SUP] 1 [/SUP], Muhammad Suleman[SUP] 2 [/SUP], Abdullah Shah[SUP] 3 [/SUP], Emmanuel Enoch Dzakah[SUP] 4 [/SUP], Shuyi Chen[SUP] 5 [/SUP], Haiying Wang[SUP] 5 [/SUP], Shixing Tang[SUP] 1 5 6 [/SUP]
Affiliations
Abstract
Mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have made this virus more infectious. Previous studies have confirmed that non-structural protein 13 (NSP13) plays an important role in immune evasion by physically interacting with TANK binding kinase 1 (TBK1) to inhibit IFNβ production. Mutations have been reported in NSP13; hence, in the current study, biophysical and structural modeling methodologies were adapted to dissect the influence of major mutations in NSP13, i.e., P77L, Q88H, D260Y, E341D, and M429I, on its binding to the TBK1 and to escape the human immune system. The results revealed that these mutations significantly affected the binding of NSP13 and TBK1 by altering the hydrogen bonding network and dynamic structural features. The stability, flexibility, and compactness of these mutants displayed different dynamic features, which are the basis for immune evasion. Moreover, the binding was further validated using the MM/GBSA approach, revealing that these mutations have higher binding energies than the wild-type (WT) NSP13 protein. These findings thus justify the basis of stronger interactions and evasion for these NSP13 mutants. In conclusion, the current findings explored the key features of the NSP13 WT and its mutant complexes, which can be used to design structure-based inhibitors against the SARS-CoV-2 new variants to rescue the host immune system.
Keywords: MD simulations; NSP13 mutants; SARS-CoV-2; TBK1; protein-protein docking.
. 2021 Dec 1;12:789062.
doi: 10.3389/fmicb.2021.789062. eCollection 2021.
Structural Analysis on the Severe Acute Respiratory Syndrome Coronavirus 2 Non-structural Protein 13 Mutants Revealed Altered Bonding Network With TANK Binding Kinase 1 to Evade Host Immune System
Farooq Rashid[SUP] 1 [/SUP], Muhammad Suleman[SUP] 2 [/SUP], Abdullah Shah[SUP] 3 [/SUP], Emmanuel Enoch Dzakah[SUP] 4 [/SUP], Shuyi Chen[SUP] 5 [/SUP], Haiying Wang[SUP] 5 [/SUP], Shixing Tang[SUP] 1 5 6 [/SUP]
Affiliations
- PMID: 34925297
- PMCID: PMC8671833
- DOI: 10.3389/fmicb.2021.789062
Abstract
Mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have made this virus more infectious. Previous studies have confirmed that non-structural protein 13 (NSP13) plays an important role in immune evasion by physically interacting with TANK binding kinase 1 (TBK1) to inhibit IFNβ production. Mutations have been reported in NSP13; hence, in the current study, biophysical and structural modeling methodologies were adapted to dissect the influence of major mutations in NSP13, i.e., P77L, Q88H, D260Y, E341D, and M429I, on its binding to the TBK1 and to escape the human immune system. The results revealed that these mutations significantly affected the binding of NSP13 and TBK1 by altering the hydrogen bonding network and dynamic structural features. The stability, flexibility, and compactness of these mutants displayed different dynamic features, which are the basis for immune evasion. Moreover, the binding was further validated using the MM/GBSA approach, revealing that these mutations have higher binding energies than the wild-type (WT) NSP13 protein. These findings thus justify the basis of stronger interactions and evasion for these NSP13 mutants. In conclusion, the current findings explored the key features of the NSP13 WT and its mutant complexes, which can be used to design structure-based inhibitors against the SARS-CoV-2 new variants to rescue the host immune system.
Keywords: MD simulations; NSP13 mutants; SARS-CoV-2; TBK1; protein-protein docking.