Effects of the Q80K Polymorphism on the Physicochemical Properties of Hepatitis C Virus Subtype 1a NS3 Protease

Hepatitis C virus genotype 1a (HCV-1a) comprises clades I and II. The Q80K polymorphism is found predominantly in clade I but rarely in clade II. Here, we investigated whether natural polymorphisms in HCV-1a clade II entailed structural protein changes when occurrence of the Q80K variant was simulat...

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Bibliographic Details
Published in:Viruses 2019-07, Vol.11 (8), p.691
Main Authors: Peres-da-Silva, Allan, Antunes, Deborah, Quintanilha Torres, André Luiz, Caffarena, Ernesto Raul, Lampe, Elisabeth
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Amino acids
Coffee
Drug resistance
Gene polymorphism
Gene Regulatory Networks
Genomes
Genotype
Hepacivirus - enzymology
Hepacivirus - genetics
Hepatitis
Hepatitis C
hepatitis C virus
Models, Molecular
molecular dynamics
Molecular Dynamics Simulation
network analysis
NS3 protease
Phylogenetics
Physicochemical properties
Polymorphism
Polymorphism, Genetic
polymorphisms
Protein structure
Proteinase
Proteins
Q80K variant
Serine Proteases - chemistry
Serine Proteases - genetics
Simulation
Viral Nonstructural Proteins - chemistry
Viral Nonstructural Proteins - genetics
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Summary:Hepatitis C virus genotype 1a (HCV-1a) comprises clades I and II. The Q80K polymorphism is found predominantly in clade I but rarely in clade II. Here, we investigated whether natural polymorphisms in HCV-1a clade II entailed structural protein changes when occurrence of the Q80K variant was simulated. Based on HCV-1a clade I and II protein sequences, the structure of the HCV-1a Q80K mutant NS3-4A was obtained by comparative modeling. Its physicochemical properties were studied by molecular dynamics simulations and network analysis. Results demonstrate that, in the presence of the K80 variant, clade II protease polymorphisms A91 and S/G174 led to variations in hydrogen bond occupancies. Structural analyses revealed differences in (i) flexibility of the H57 catalytic residue on the NS3 protease and (ii) correlations between amino acids on the NS3 protease and the NS4A cofactor. The latter indicated possible destabilization of interactions, resulting in increased separation of these proteins. The present findings describe how the relationships between different HCV-1a NS3 protease amino acid residues could affect the appearance of viral variants and the existence of distinct genetic barriers to HCV-1a isolates.
ISSN:1999-4915
1999-4915
DOI:10.3390/v11080691