D155Y substitution of SARS-CoV-2 ORF3a weakens binding with Caveolin-1.
Comput Struct Biotechnol J
; 20: 766-778, 2022.
Article
in English
| MEDLINE | ID: covidwho-2261663
ABSTRACT
The clinical manifestation of the recent pandemic COVID-19, caused by the novel SARS-CoV-2 virus, varies from mild to severe respiratory illness. Although environmental, demographic and co-morbidity factors have an impact on the severity of the disease, contribution of the mutations in each of the viral genes towards the degree of severity needs a deeper understanding for designing a better therapeutic approach against COVID-19. Open Reading Frame-3a (ORF3a) protein has been found to be mutated at several positions. In this work, we have studied the effect of one of the most frequently occurring mutants, D155Y of ORF3a protein, found in Indian COVID-19 patients. Using computational simulations we demonstrated that the substitution at 155th changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein compared with the other substitutions found in Indian patients. Protein-protein docking using HADDOCK analysis revealed that substitution D155Y weakened the binding affinity of ORF3a with caveolin-1 compared with the other substitutions, suggesting its importance in the overall stability of ORF3a-caveolin-1 complex, which may modulate the virulence property of SARS-CoV-2.
ARL6IP6, ADP Ribosylation Factor Like GTPase 6 interacting protein 6; ASC, Apoptosis associated speck-like protein containing a caspase recruitment domain; BLAST, Basic Local Alignment Search Tool; CD4+, Cluster of Differentiation 4+; CD8+, Cluster of Differentiation 8+; COVID-19, Coronavirus Disease 2019; Caveolin-1; Cryo-EM, Cryo Electron Microscope; Graph theory; HMOX1, Heme Oxygenase 1; IFN, Interferon; MERS-CoV, Middle East respiratory syndrome coronavirus; MMGBSA, Molecular mechanics with generalized Born and surface area solvation; Molecular dynamics simulation; Mutation; NCBI, National Centre for Biotechnology Information; NF-<ns0:math> <mrow> <mi>κ</mi> </mrow> </math>B, Nuclear factor kappa light chain enhancer of activated B cells; NLRP3, Nucleotide-binding oligomerization domain, Leucine rich repeat and Pyrin domain containing; ORF, Open Reading Frame; ORF3a; PDB, Protein Data Bank; PISA, Protein Interfaces Surfaces and Assemblies; PROVEAN, Protein Variation Effect Analyzer; RMSD, Root Mean Square Deviation; SARS-CoV-2; SUN2, SUN domain-containing protein 2; TRIM59, Tripartite motif-containing protein 59.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Type of study:
Prognostic study
Language:
English
Journal:
Comput Struct Biotechnol J
Year:
2022
Document Type:
Article
Affiliation country:
J.csbj.2022.01.017
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