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Molecular modeling of swine influenza A/H1N1, Spanish H1N1, and avian H5N1 flu N1 neuraminidases bound to Tamiflu and Relenza.

ABSTRACT: A molecular model of the swine influenza A/H1N1 ( also called H1N1pdm) type-I neuraminidase was built using the pathogenic avian H5N1 type-I neuraminidase as a basis, due to the higher sequence identity between A/H1N1 and H5N1 (91.47%) compared to Spanish H1N1 (88.37%) neuraminidase. All-atom molecular dynamics (MD) simulations of all three neuraminidases were performed, either as apo-structures or with commercial antiviral drugs Tamiflu or Relenza separately bound; the simulations allowed for the identification of both conserved and unique drug-protein interactions across all three proteins. Specifically, conserved networks of hydrogen bonds stabilizing the drugs in the sialic acid binding site of the simulated neuraminidases are analyzed, providing insight into how disruption due to mutations may lead to increased drug resistance. In addition, a possible mechanism through which the residue 294 mutation acquires drug resistance is proposed by mapping the mutation site onto an electrostatic pathway which may play a role in controlling drug access to the binding pocket of neuraminidase, establishing a starting point for further investigations of neuraminidase drug resistance.

SUBMITTER: Le L

PROVIDER: S-EPMC2762416 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCatalytic activity of influenza neuraminidase (NA) facilitates elution of progeny virions from infected cells and prevents their self-aggregation mediated by the catalytic site located in the body region. Research on the active site of the molecule has led to development of effective inhibitors like oseltamivir, zanamivir etc, but the high rate of mutation and interspecies reassortment in viral sequences and the recent reports of oseltamivir resistant strains underlines the importance of determining additional target sites for developing future antiviral compounds. In a recent computational study of 173 H5N1 NA gene sequences we had identified a 50-base highly conserved region in 3'-terminal end of the NA gene.ResultsWe extend the graphical and numerical analyses to a larger number of H5N1 NA sequences (514) and H1N1 swine flu sequences (425) accessed from GenBank. We use a 2D graphical representation model for the gene sequences and a Graphical Sliding Window Method (GSWM) for protein sequences scanning the sequences as a block of 16 amino acids at a time. Using a protein sequence descriptor defined in our model, the protein sliding scan method allowed us to compare the different strains for block level variability, which showed significant statistical correlation to average solvent accessibility of the residue blocks; single amino acid position variability results in no correlation, indicating the impact of stretch variability in chemical environment. Close to the C-terminal end the GSWM showed less descriptor-variability with increased average solvent accessibility (ASA) that is also supported by conserved predicted secondary structure of 3' terminal RNA and visual evidence from 3D crystallographic structure.ConclusionThe identified terminal segment, strongly conserved in both RNA and protein sequences, is especially significant as it is surface exposed and structural chemistry reveals the probable role of this stretch in tetrameric stabilization. It could also participate in other biological processes associated with conserved surface residues. A RNA double hairpin secondary structure found in this segment in a majority of the H5N1 strains also supports this observation. In this paper we propose this conserved region as a probable site for designing inhibitors for broad-spectrum pandemic control of flu viruses with similar NA structure.

Project description:ObjectivesThe main function of influenza neuraminidase (NA) involves enzymatic cleavage of sialic acid from the surface of host cells resulting in the release of the newly produced virions from infected cells, as well as aiding the movement of virions through sialylated mucus present in the respiratory tract. However, there has previously been little information on the binding affinity of different forms of sialylated glycan with NA. Our objectives were then to investigate both sialic acid binding and cleavage of neuraminidase at an atomic resolution level.DesignNuclear magnetic resonance (NMR) spectroscopy was used to investigate pH and temperature effects on binding and cleavage as well as to interrogate the selectivity of human-like or avian-like receptors for influenza neuraminidase N1 derived from a range of different influenza virus strains including human seasonal H1N1, H1N1pdm09 and avian H5N1.ResultsWe demonstrated that an acidic pH and physiological temperature are required for efficient NA enzymatic activity; however a change in the pH had a minimum effect on the NA-sialic acid binding affinity. Our data comparing ?-2,3- and ?-2,6-sialyllactose indicated that the variation in neuraminidase activity on different ligands correlated with a change in binding affinity. Epitope mapping of the sialylglycans interacting with NAs from different viral origin showed different binding profiles suggesting that different binding conformations were adopted.ConclusionsThe data presented in this study demonstrated that physicochemical conditions (pH in particular) could affect the NA enzymatic activity with minor effect on ligand binding. NA cleavage specificity seemed to be associated with a difference in binding affinity to different ligands, suggesting a relationship between the two events. These findings have implications regarding the replication cycle of influenza infection in the host where different sialidase activities would influence penetration through the respiratory mucin barrier and the release of the newly generated virus from the infected cells.

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Molecular modeling of swine influenza A/H1N1, Spanish H1N1, and avian H5N1 flu N1 neuraminidases bound to Tamiflu and Relenza.

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