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Impact of tetramerization on the ligand recognition of N1 influenza neuraminidase via MMGBSA approach
Author(s) -
Bello Martiniano
Publication year - 2019
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.23251
Subject(s) - chemistry , neuraminidase , sialic acid , ligand (biochemistry) , cooperativity , monomer , stereochemistry , substrate (aquarium) , molecular dynamics , combinatorial chemistry , enzyme , biochemistry , computational chemistry , receptor , organic chemistry , polymer , oceanography , geology
Abstract Influenza virus neuraminidase (NA) is a homotetrameric surface protein that, in contrast to other non‐influenza NAs, requires a quaternary assembly to exhibit enzymatic activity, suggesting that the oligomeric state significantly impacts the active site of influenza NA. Nevertheless, most structure‐based drug design studies have been reported by employing the monomeric state in the closed or open‐loop due to the computational cost of employing the tetrameric NA. In this work, we present MD simulations coupled to the MMGBSA approach of avian N1 type NA in its monomeric and tetrameric closed and open‐loop state both with and without the inhibitor oseltamivir and its natural substrate, sialic acid. Structural and energetic analyses revealed that the tetrameric state impacts flexibility as well as the map of interactions participating in stabilizing the protein–ligand complexes with respect to the monomeric state. It was observed that the tetrameric state exerts dissimilar effects in binding affinity, characteristic of positive and negative cooperativity for oseltamivir and sialic acid, respectively. Based on our results, to perform a confident structure‐based drug design, as well as to evaluate the impact of key mutations through MD simulations, it is important to consider the tetrameric state closed‐loop state.