Abstract
Influenza A viruses are highly contagious RNA viruses that cause respiratory tract infections in humans and animals. Their non-structural protein NS1, a homodimer of two 230-residue chains, is the main viral factor in counteracting the antiviral defenses of the host cell. Its RNA-binding domain is an obligate dimer that is connected to each of the two effector domains by a highly flexible unstructured linker region of ten amino acids. The flexibility of NS1 is a key property that allows its effector domains and its RNA binding domain to interact with several protein partners or RNAs. The three-dimensional structures of full-length NS1 dimers revealed that the effector domains could adopt three distinct conformations as regards their mutual interactions and their orientation relative to the RNA binding domain (closed, semi-open and open). The origin of this structural polymorphism is currently being investigated and several hypotheses are proposed, among which one posits that it is a strain-specific property. In the present study, we explored through computational molecular modeling the dynamic and flexibility properties of NS1 from three important influenza virus A strains belonging to three distinct subtypes (H1N1, H6N6, H5N1), for which at least one conformation is available in the Protein Data Bank. In order to verify whether NS1 is stable in three forms for the three strains, we constructed homology models if the corresponding forms were not available in the Protein Data Bank. Molecular dynamics simulations were performed in order to predict the stability over time of the three distinct sequence variants of NS1, in each of their three distinct conformations. Our results favor the co-existence of three stable structural forms, regardless of the strain, but also suggest that the length of the linker, along with the presence of specific amino acids, modulate the dynamic properties and the flexibility of NS1.
Highlights
Influenza A viruses (IAVs) are highly contagious RNA viruses that cause respiratory tract infections in humans and animals
We focused on the structural polymorphism of non-structural protein 1 (NS1) for three strains with full length structures available in the Protein Data Bank (PDB)
Based on the results of this study, we showed that NS1 in the closed form exhibits high stability in molecular dynamics simulations with a stable effector domain (ED)–ED dimerization interface that involves the strands of the beta-sheets
Summary
Influenza A viruses (IAVs) are highly contagious RNA viruses that cause respiratory tract infections in humans and animals. Seasonal influenza causes three to five million severe cases and 290,000 to 650,000 deaths due to respiratory complications [1,2]. NS1 plays an important role in countering the antiviral defenses of the infected cell, thereby helping the virus to escape the innate immune system [3,4]. For this reason, novel therapeutic strategies have recently been explored that antagonize NS1’s activities [5,6]. The effector domain is proving to be an important therapeutic target given its multiple protein partners and its role in the structural polymorphism of NS1 [6,8,9]
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