Molecular modeling studies demonstrate key mutations that could affect the ligand recognition by influenza AH1N1 neuraminidase

Abstract

The goal of this study was to identify neuraminidase (NA) residue mutants from human influenza AH1N1 using sequences from 1918 to 2012. Multiple alignment studies of complete NA sequences (5732) were performed. Subsequently, the crystallographic structure of the 1918 influenza (PDB ID: 3BEQ-A) was used as a wild-type structure and three-dimensional (3-D) template for homology modeling of the mutated selected NA sequences. The 3-D mutated NAs were refined using molecular dynamics (MD) simulations (50 ns). The refined 3-D models were used to perform docking studies using oseltamivir. Multiple sequence alignment studies showed seven representative mutations (A232V, K262R, V263I, T264V, S367L, S369N, and S369K). MD simulations applied to 3-D NAs showed that each NA had different active-site shapes according to structural surface visualization and docking results. Moreover, Cartesian principal component analyses (cPCA) show structural differences among these NA structures caused by mutations. These theoretical results suggest that the selected mutations that are located outside of the active site of NA could affect oseltamivir recognition and could be associated with resistance to oseltamivir.

Whole Genome Sequencing of A(H3N2) Influenza Viruses Reveals Variants Associated with Severity during the 2016–2017 Season

“…To the best of our knowledge, NA V263I has not been studied in an H3N2 background yet. However, a comprehensive study of NA V263I involvement at the structural level suggested the isoleucine, which is two methyl groups higher than a valine, could allow important changes by altering hindrance effects [37]. It was also suggested that this site was part of an epitope that was suitable for therapeutic monoclonal antibodies, and that an amino acid change at this position modified the immune response [38].…”

The significance of naturally occurring neuraminidase quasispecies of H5N1 avian influenza virus on resistance to oseltamivir: a point of concern

“…Mutations located at the binding site can affect the structural and/or functional behaviour of the protein. However, mutations located outside the binding site could possibly alter the structure of the binding pocket and, thus, could be associated with drug resistance (Ramírez-Salinas et al, 2015). Kar & Knecht (2012) suggested that the binding pockets of the mutated N8 NAs were less flexible as compared with the binding pocket of the WT protein.…”