Accession Number ADA571136
Title Quantitative Predictions of Binding Free Energy Changes in Drug- Resistant Influenza Neuraminidase.
Publication Date Aug 2012
Media Count 12p
Personal Author D. R. Ripoll I. V. Khavrutskii J. Liu R. A. Kuschner S. Chaudhury
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 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.
Keywords Antiviral agents
Binding free energy
Drug resistance
Free energy
Hamiltonian replica exchanges
Hydrogen bonds
Hydrophobic properties
Molecular dynamics
Neuraminic acid
Receptor sites(Physiology)
Srmm(Single-reference multiple mutants)
Srsm(Single reference single mutant)
Srti(Single reference thermodynamic integration)

Source Agency Non Paid ADAS
NTIS Subject Category 57Q - Pharmacology & Pharmacological Chemistry
Corporate Author Army Medical Research and Materiel Command (Provisional), Fort Detrick, MD. Telemedicine and Advanced Tech Research Center.
Document Type Journal article
Title Note Journal article.
NTIS Issue Number 1315
Contract Number N/A

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