Influenza A virus neuraminidase-GRP78 binding site prediction

Previous research has shown that there is an interaction between Influenza A viral surface neuraminidase (NA) and the host endoplasmic reticulum chaperone GRP78 in the early phases of NA production in the endoplasmic reticulum. In this study, we predict the binding sites of neuraminidase for H1N1, H3N2, and H5N1 strains. We select 13 conserved, cysteine-cyclized regions, one of which is hypothesized to be a possible binding site for GRP78. Using the grand average hydrophobicity index (GRAVY), we focus only on specific highlighted hydrophobic regions, which match the profile of the cyclic peptide, Pep42. Protein-protein docking analysis using HADDOCK suggests that region VIII (C278:C291) is the best possible binding site with the substrate-binding domain β (SBDβ) of GRP78. Subsequently, MDS runs for 150 ns are conducted, and MM-GBSA calculations are done for the three complexes (-7.10, -22.22, and -11.26 kcal/mol for H1N1, H3N2, and H5N1, respectively). The results indicate that GRP78 remains associated with the NA of H3N2, whereas the NAs of H1N1 and H5N1 dissociate from GRP78 during the simulation. Our findings show that region VIII is a potential therapeutic target for neutralizing the viral neuraminidase of seasonal H3N2 flu.