TY - JOUR
T1 - Quantitative Predictions of Binding Free Energy Changes in Drug-Resistant Influenza Neuraminidase
AU - Ripoll, Daniel R.
AU - Khavrutskii, Ilja V.
AU - Chaudhury, Sidhartha
AU - Liu, Jin
AU - Kuschner, Robert A.
AU - Wallqvist, Anders
AU - Reifman, Jaques
PY - 2012/8
Y1 - 2012/8
N2 - Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 μs of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.
AB - Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD) with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 μs of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.
UR - http://www.scopus.com/inward/record.url?scp=84866086808&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1002665
DO - 10.1371/journal.pcbi.1002665
M3 - Article
C2 - 22956900
AN - SCOPUS:84866086808
SN - 1553-734X
VL - 8
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 8
M1 - e1002665
ER -