Quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase.

ABSTRACT: 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 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations

SUBMITTER: Ripoll DR 

PROVIDER: S-EPMC3431292 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature