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Outside-binding site mutations modify the active site's shapes in neuraminidase from influenza A H1N1

Authors

  • Luis Tolentino-Lopez,

    1. Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, México City 11340, México
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  • Aldo Segura-Cabrera,

    1. Laboratorio de Bioinformática, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro esquina Elías Piña, Colonia Narciso Mendoza, 88710, Ciudad Reynosa, Tamaulipas, México
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  • Paola Reyes-Loyola,

    1. Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, México City 11340, México
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  • Mirko Zimic,

    1. Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, San Martín de Porres, Lima, Perú
    2. Drug R&D Unit, Center for Applied Pharmacobiology Research, University of Navarra, C/ Irunlarrea s/n, 31008 Pamplona, Spain
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  • Miguel Quiliano,

    1. Laboratorio de Bioinformática y Biología Molecular, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, San Martín de Porres, Lima, Perú
    2. Drug R&D Unit, Center for Applied Pharmacobiology Research, University of Navarra, C/ Irunlarrea s/n, 31008 Pamplona, Spain
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  • Veronica Briz,

    1. Laboratorio de Inmunobiología Molecular, Hospital Universitario Gregorio Marañón, Madrid, España
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  • Angeles Muñoz-Fernández,

    1. Laboratorio de Inmunobiología Molecular, Hospital Universitario Gregorio Marañón, Madrid, España
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  • Mario Rodríguez-Pérez,

    1. Laboratorio de Biomedicina Molecular, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro esquina Elías Piña, Colonia Narciso Mendoza, 88710, Ciudad Reynosa, Tamaulipas, México
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  • Ian Ilizaliturri-Flores,

    1. Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, México City 11340, México
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  • Jose Correa-Basurto

    Corresponding author
    1. Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, México City 11340, México
    • Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, México City 11340, México
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  • This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Abstract

The recent occurrence of 2009 influenza A (H1N1) pandemic as well as others has raised concern of a far more dangerous outcome should this virus becomes resistant to current drug therapies. The number of clinical cases that are resistant to oseltamivir (Tamiflu®) is larger than the limited number of neuraminidase (NA) mutations (H275Y, N295S, and I223R) that have been identified at the active site and that are associated to oseltamivir resistance. In this study, we have performed a comparative analysis between a set of NAs that have the most representative mutations located outside the active site. The recently crystallized NA-oseltamivir complex (PDB ID: 3NSS) was used as a wild-type structure. After selecting the target NA sequences, their three-dimensional (3D) structure was built using 3NSS as a template by homology modeling. The 3D NA models were refined by molecular dynamics (MD) simulations. The refined models were used to perform a docking study, using oseltamivir as a ligand. Furthermore, the docking results were refined by free-energy analysis using the MM-PBSA method. The analysis of the MD simulation results showed that the NA models reached convergence during the first 10 ns. Visual inspection and structural measures showed that the mutated NA active sites show structural variations. The docking and MM-PBSA results from the complexes showed different binding modes and free energy values. These results suggest that distant mutations located outside the active site of NA affect its structure and could be considered to be a new source of resistance to oseltamivir, which agrees with reports in the clinical literature. © 2012 Wiley Periodicals, Inc.

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