title: Role of R292K mutation in influenza H7N9 neuraminidase toward oseltamivir susceptibility: MD and MM/PB(GB)SA study.
abstract: The H7N9 avian influenza virus is a novel re-assortment from at least four different strains of virus. Neuraminidase, which is a glycoprotein on the surface membrane, has been the target for drug treatment. However, some H7N9 strains that have been isolated from patient after drug treatment have a R292K mutation in neuraminidase. This substitution was found to facilitate drug resistance using protein- and virus- assays, in particular it gave a high resistance to the most commonly used drug, oseltamivir. The aim of this research is to understand the source of oseltamivir resistance using MD simulations and the MM/PB(GB)SA binding free energy approaches. Both methods can predict the reduced susceptibility of oseltamivir in good agreement to the IC50binding energy, although MM/GBSA underestimates this prediction compared to the MM/PBSA calculation. Electrostatic interaction is the main contribution for oseltamivir binding in terms of both interaction and solvation. We found that the source of the drug resistance is a decrease in the binding interaction combined with the reduction of the dehydration penalty. The smaller K292 mutated residue has a larger binding pocket cavity compared to the wild-type resulting in the loss of drug carboxylate-K292 hydrogen bonding and an increased accessibility for water molecules around the K292 mutated residue. In addition, oseltamivir does not bind well to the R292K mutant complex as shown by the high degree of fluctuation in ligand RMSD during the simulation and the change in angular distribution of bulky side chain groups.
authors.affiliation: Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
authors.forename: Jiraphorn
authors.initials: J
authors.lastname: Phanich
authors.affiliation: Structural and Computational Biology Research Group, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. t.rungrotmongkol@gmail.com.|Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. t.rungrotmongkol@gmail.com.
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.affiliation: Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand.
authors.forename: Nawee
authors.initials: N
authors.lastname: Kungwan
authors.affiliation: Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand. supot.h@chula.ac.th.
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D001665:Binding Sites; D055808:Drug Discovery; D024882:Drug Resistance, Viral; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000201:enzymology*; D007251:Influenza, Human; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009154:Mutation; D009439:Neuraminidase / Q000737:chemistry* / Q000235:genetics; D053139:Oseltamivir / Q000737:chemistry*; D011485:Protein Binding; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase
keywords: H7N9 influenza neuraminidase; MM/PB(GB)SA; Molecular dynamics simulation; R292K mutant