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

• Published in: Journal of molecular modeling Vol. 21; no. 11; p. 292
• Main Authors: Ramírez-Salinas, Gema L., García-Machorro, J., Quiliano, Miguel, Zimic, Mirko, Briz, Verónica, Rojas-Hernández, Saul, Correa-Basurto, J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2015
• Subjects: Amino Acid Sequence; Binding Sites; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Influenza A Virus, H1N1 Subtype - enzymology; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Medicine; Neuraminidase - chemistry; Original Paper; Point Mutation; Principal Component Analysis; Protein Structure, Tertiary; Theoretical and Computational Chemistry; Viral Proteins - chemistry; Mutations; Docking; Molecular dynamics simulations; Influenza A H1N1; Neuraminidase
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-015-2835-6

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.