Molecular modeling studies demonstrate key mutations that could affect the ligand recognition by influenza AH1N1 neuraminidase.
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.
Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, México City, Mexico.
Gema L
GL
Ramírez-Salinas
Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Mexico, DF, 11340, México.
J
J
García-Machorro
Unidad de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Universidad Peruana Cayetano Heredia, Lima, Perú
Miguel
M
Quiliano
Unidad de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Universidad Peruana Cayetano Heredia, Lima, Perú
Mirko
M
Zimic
Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, España.
Verónica
V
Briz
Laboratory of Immunology, School of Medicine, National Polytechnic Institute, Mexico, DF, Mexico.
Saul
S
Rojas-Hernández
Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, México City, Mexico. corrjose@gmail.com.
J
J
Correa-Basurto
D000595:Amino Acid Sequence; D001665:Binding Sites; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology*; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000737:chemistry*; D017354:Point Mutation; D025341:Principal Component Analysis; D017434:Protein Structure, Tertiary; D014764:Viral Proteins / Q000737:chemistry*
D008024:Ligands; D014764:Viral Proteins; D009439:Neuraminidase
Docking; Influenza A H1N1; Molecular dynamics simulations; Mutations; Neuraminidase