TY - JOUR
T1 - Impact of tetramerization on the ligand recognition of N1 influenza neuraminidase via MMGBSA approach
AU - Bello, Martiniano
N1 - Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Binding free energy
KW - Influenza virus neuraminidase
KW - Molecular dynamics simulations
KW - Oseltamivir
KW - Sialic acid
UR - http://www.scopus.com/inward/record.url?scp=85059146518&partnerID=8YFLogxK
U2 - 10.1002/bip.23251
DO - 10.1002/bip.23251
M3 - Artículo
C2 - 30589081
SN - 0006-3525
VL - 110
JO - Biopolymers
JF - Biopolymers
IS - 5
M1 - e23251
ER -