D155Y substitution of SARS-CoV-2 ORF3a weakens binding with Caveolin-1

https://doi.org/10.1016/j.csbj.2022.01.017Get rights and content
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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.

Abbreviations

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
Cryo-EM
Cryo Electron Microscope
HMOX1
Heme Oxygenase 1
IFN
Interferon
MERS-CoV
Middle East respiratory syndrome coronavirus
MMGBSA
Molecular mechanics with generalized Born and surface area solvation
NCBI
National Centre for Biotechnology Information
NF-κB
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
PDB
Protein Data Bank
PISA
Protein Interfaces Surfaces and Assemblies
PROVEAN
Protein Variation Effect Analyzer
RMSD
Root Mean Square Deviation
SUN2
SUN domain-containing protein 2
TRIM59
Tripartite motif-containing protein 59.

Keywords

ORF3a
SARS-CoV-2
Molecular dynamics simulation
Graph theory
Mutation
Caveolin-1

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The authors equally contributed to this paper.