TITLE:

FIGHTING INFLUENZA VIRUSES USING SUPER COMPUTERS

DATE:

Friday, November 21, 2008

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

Dong Xu, NIH Center of National Biomedical Computation Resource, McCammon Group/Dept. of Chemistry and Biochemistry ,University of California, San Diego

ABSTRACT:

The new highly lethal avian influenza virus strains H5N1 poses a serious pandemic threat. Continuing evolution of influenza viruses through mutations and gene reassortment causes drug resistance and receptor binding specificity switch which may enable efficient human transmission. Development of new anti-viral drugs and rapid detection techniques of binding specificity switch are essential. We employed explicitly and implicitly solvated molecular dynamics (MD) simulations to study the structural flexibility of influenza virus surface proteins Hemagglutinin (HA) and and Neuraminidase (NA) that are responsible for the attachment and releasing of viral particles to and from the host cells. The NA simulations revealed remarkable loop flexibility in N1, opening new cavities adjacent to the catalytic active site. Subsequent ensemble-based virtual screening identified top 27 compounds, some of which effectively exploit the expanded binding pocket and may be potent novel inhibitors. The absolute binding free energies of Tamiflu bound to N1 and N9 were also analyzed using MM-GBSA scheme and the results trend well with experimental data. The HA simulations examined the topological and energetic characteristics of avian and human receptor analogs in complex with 3 different HA subtypes, H3, H5 and H9. The findings offer insight to the key HA-glycan interactions and suggest new strategies for monitoring viral host range selection by different influenza viruses.

HOST:

Andy Cooksy

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