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.
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References
Kao CL, Chan TC et al. (2012) Emerged HA and NA mutants of the pandemic influenza H1N1 viruses with increasing epidemiological significance in Taipei and Kaohsiung, Taiwan, 2009–10. PLoS ONE 7(2):e31162
Pan P, Li L, Li Y, Li D, Hou T (2013) Insights into susceptibility of antiviral drugs against the E119G mutant of 2009 influenza A (H1N1) neuraminidase by molecular dynamics simulations and free energy calculations. Antivir Res 100(2):356–364
Quiliano M, Valdivia-Olarte H, Olivares C, Requena D, Gutiérrez AH, Reyes-Loyola P, Tolentino-Lopez LE, Sheen P, Briz V, Muñoz-Fernández MA, Correa-Basurto J, Zimic M (2013) Molecular distribution of amino acid substitutions on neuraminidase from the 2009 (H1N1) human influenza pandemic virus. Bioinformation 9(13):673–679
Collins PJ, Haire LF et al. (2008) Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature 453(7199):1258–1261
Wang NX, Zheng JJ (2009) Computational studies of H5N1 influenza virus resistance to oseltamivir. Protein Sci 18(4):707–715
Woods CJ, Malaisree M et al. (2012) Long time scale GPU dynamics reveal the mechanism of drug resistance of the dual mutant I223R/H275Y neuraminidase from H1N1-2009 influenza virus. Biochemistry 51(21):4364–4375
Tolentino-Lopez L, Segura-Cabrera A et al. (2012) Outside-binding site mutations modify the active site's shapes in neuraminidase from influenza A H1N1. Biopolymers 99(1):10–21
Sheu TG, Fry AM et al. (2011) Dual resistance to adamantanes and oseltamivir among seasonal influenza A(H1N1) viruses: 2008–2010. J Infect Dis 203(1):13–17
Esposito S, Molteni CG et al. (2010) Clinical importance and impact on the households of oseltamivir-resistant seasonal A/H1N1 influenza virus in healthy children in Italy. Virol J 7:202
Govorkova EA, Ilyushina NA et al. (2010) Competitive fitness of oseltamivir-sensitive and -resistant highly pathogenic H5N1 influenza viruses in a ferret model. J Virol 84(16):8042–8050
Loyola PK, Campos-Rodríguez R, Bello M, Rojas-Hernández S, Zimic M, Quiliano M, Briz V, Muñoz-Fernández MA, Tolentino-López L, Correa-Basurto J (2013) Theoretical analysis of the neuraminidase epitope of the Mexican A H1N1 influenza strain, and experimental studies on its interaction with rabbit and human hosts. Immunol Res doi: 10.1007/s12026-013-8385-z
Zepeda HM, Perea-Araujo L et al. (2010) Identification of influenza A pandemic (H1N1) 2009 variants during the first 2009 influenza outbreak in Mexico City. J Clin Virol 48(1):36–39
Bearman GM, Shankaran S et al. (2010) Treatment of severe cases of pandemic (H1N1) 2009 influenza: review of antivirals and adjuvant therapy. Recent Pat Antiinfect Drug Discov 5(2):152–156
Memoli MJ, Hrabal RJ et al. (2010) Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts. Clin Infect Dis 50(9):1252–1255
Pizzorno A, Bouhy X et al. (2011) Generation and characterization of recombinant pandemic influenza A(H1N1) viruses resistant to neuraminidase inhibitors. J Infect Dis 203(1):25–31
Kim D, Lyoo KS et al. (2011) Number of mutations within CTL-defined epitopes of the hepatitis B Virus (HBV) core region is associated with HBV disease progression. J Med Virol 83(12):2082–2087
Tanaka M, Kato A et al. (2012) Herpes simplex virus 1 VP22 regulates translocation of multiple viral and cellular proteins and promotes neurovirulence. J Virol 86(9):5264–5277
Strengell M, Ikonen N et al. (2011) Minor changes in the hemagglutinin of influenza A(H1N1)2009 virus alter its antigenic properties. PLoS ONE 6(10):e25848
Cuevas JM, Delaunay A et al. (2012) Molecular evolution and phylogeography of potato virus Y based on the CP gene. J Gen Virol 93(Pt 11):2496–2501
Zhong S, MacKerell AD Jr (2007) Binding response: a descriptor for selecting ligand binding site on protein surfaces. J Chem Inf Model 47(6):2303–2315
Navarro-Polanco RA, Moreno Galindo EG et al. (2011) Conformational changes in the M2 muscarinic receptor induced by membrane voltage and agonist binding. J Physiol 589(Pt 7):1741–1753
Vijayan R, Sahai MA et al. (2010) A comparative analysis of the role of water in the binding pockets of ionotropic glutamate receptors. Phys Chem Chem Phys 12(42):14057–14066
Demina A, Varughese KI et al. (1998) Six previously undescribed pyruvate kinase mutations causing enzyme deficiency. Blood 92(2):647–652
Edgar RC (2004) MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinforma 5:113
Larkin MA, Blackshields G et al. (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23(21):2947–2948
Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234(3):779–815
Soriano-Ursua MA, Correa-Basurto J et al. (2011) Homology model and docking studies on porcine beta(2) adrenoceptor: description of two binding sites. J Mol Model 17(10):2525–2538
Phillips JC, Braun R et al. (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26(16):1781–1802
MacKerell AD Jr, Bashford D et al. (1998) All-atom empirical potential for molecular modeling and dynamics Studies of proteins. J Phys Chem B 102(3586):3616
Humphrey W, Dalke A et al. (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38, 27–38
Feller SE, Zhang YH, Pastor RW, Brooks BR (1995) Constant-pressure molecular-dynamics simulation—the Langevin piston method. J Chem Phys 103(11):4613–4621
Martyna GJ, Tobias DJ et al. (1994) Constant pressure molecular dynamics simulations. J Chem Phys 101:4177–4189
Batcho PF, Case DA et al. (2001) Optimized particle-mesh Ewald/multiple-timestep integration for molecular dynamics simulations. J Chem Phys 115:4003–4018
Ryckaert JP, Ciccotti G et al. (1977) Numerical integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes. J Comput Phys 23:327–314
Glykos NM (2006) Software news and updates. Carma: a molecular dynamics analysis program. J Comput Chem 27(14):1765–1768
Amadei A, Linssen AB, Berendsen HJ (1993) Essential dynamics of proteins. Proteins 17(4):412–425
Morris GM, Goodsell DS et al. (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662
Frisch MJ, Trucks GW et al. (1998) Gaussian 98, revision A.9. Gaussian Inc, Pittsburgh
Gray, M. R. B. I. C. (2003) Bioinformatics for Geneticists.
Orozovic G, Orozovic K et al. (2011) Detection of resistance mutations to antivirals oseltamivir and zanamivir in avian influenza A viruses isolated from wild birds. PLoS ONE 6(1):e16028
Wang SQ, Du QS, Huang RB, Zhang DW, Chou KC (2009) Insights from investigating the interaction of oseltamivir (Tamiflu) with neuraminidase of the 2009H1N1 swine flu virus. Biochem Biophys Res Commun 386(3):432–436
Deeb O, Rosales-Hernandez MC et al. (2010) Exploration of human serum albumin binding sites by docking and molecular dynamics flexible ligand-protein interactions. Biopolymers 93(2):161–170
Amaro RE, Swift RV et al. (2011) Mechanism of 150-cavity formation in influenza neuraminidase. Nat Commun 2:388
Wang P, Zhang JZ (2010) Selective binding of antiinfluenza drugs and their analogues to 'open' and 'closed' conformations of H5N1 neuraminidase. J Phys Chem B 114(40):12958–12964. doi:10.1021/jp1030224
Rungrotmongkol T, Malaisree M, Udommaneethanakit T, Hannongbua S (2009) Comment on "Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)". Biophys Chem 141(1):131–132
Acknowledgments
The study was supported by grants from ICyTDF (PIRIVE09-9) CONACYT (CB- 241339), CYTED and PIFI-SIP-COFAA-IPN and scholarships to RSGL from CONACYT. Verónica Briz is supported by the Miguel Servet program from Fondo de Investigación Sanitaria (ISCIII) [grant number CP13/00098].
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Ramírez-Salinas, G.L., García-Machorro, J., Quiliano, M. et al. Molecular modeling studies demonstrate key mutations that could affect the ligand recognition by influenza AH1N1 neuraminidase. J Mol Model 21, 292 (2015). https://doi.org/10.1007/s00894-015-2835-6
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DOI: https://doi.org/10.1007/s00894-015-2835-6