Mutation-induced loop opening and energetics for binding of tamiflu to influenza N8 neuraminidase

The Journal of Physical Chemistry. B
Parimal Kar, Volker Knecht

Abstract

Tamiflu, also known as oseltamivir (OTV), binds to influenza A neuraminidase (H5N1) with very high affinity (0.32 nM). However, this inhibitor binds to other neuraminidases as well. In the present work, a systematic computational study is performed to investigate the mechanism underlying the binding of oseltamivir to N8 neuraminidase (NA) in "open" and "closed" conformations of the 150-loop through molecular dynamics simulations and the popular and well established molecular mechanics Poisson-Boltzmann (MM-PBSA) free energy calculation method. Whereas the closed conformation is stable for wild type N8, it transforms into the open conformation for the mutants Y252H, H274Y, and R292K, indicating that bound to oseltamivir these mutants are preferentially in the open conformation. Our calculations show that the binding of wild type oseltamivir to the closed conformation of N8 neuraminidase is energetically favored compared to the binding to the open conformation. We observe water mediated binding of oseltamivir to the N8 neuraminidase in both conformations which is not seen in the case of binding of the same drug to the H5N1 neuraminidase. The decomposition of the binding free energy reveals the mechanisms underlying the binding an...Continue Reading

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Citations

Sep 25, 2012·Journal of Chemical Information and Modeling·Lin LiTingjun Hou
May 12, 2012·The Journal of Physical Chemistry. B·Parimal Kar, Volker Knecht
Oct 28, 2016·Journal of Computer-aided Molecular Design·Jiraphorn PhanichSupot Hannongbua
Jan 20, 2021·Journal of Biomolecular Structure & Dynamics·Uma ShankarAmit Kumar
Jul 28, 2021·Chemometrics and Intelligent Laboratory Systems : an International Journal Sponsored by the Chemometrics Society·Vijay H MasandMagdi E A Zaki

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