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

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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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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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Correspondence to J. Correa-Basurto.

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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

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