quantitative predictions of binding free energy changes in drug-resistant influenza neuraminidase定量预测耐药流感病毒神经氨酸酶的结合自由能变化.pdfVIP

Quantitative Predictions of Binding Free Energy Changes in Drug-Resistant Influenza Neuraminidase 1 1 1 1 2 Daniel R. Ripoll , Ilja V. Khavrutskii , Sidhartha Chaudhury , Jin Liu , Robert A. Kuschner , 1 1 Anders Wallqvist , Jaques Reifman * 1 Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland, United States of America, 2 Walter Reed Army Institute of Research, Emerging Infectious Diseases Research Unit, Silver Spring, Maryland, United States of America 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 ms 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 i