MOD THE STRUCT AND DYN OF ACETYLCHOLINESTERASE CLUST- EFF ON ACETYLCHOLINE HYD

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As the Avian flu pandemic threat is looming in the horizon, existing antiviral inhibitors are likely to be of limited efficacy due to the high mutation rate of the flu virus. While there is significant investment in the pharmaceutical and biotechnology industry to develop new vaccines and new means of intervention, more fundamental research is required to understand the mechanism of action of Avian flu infectious life cycle, especially in terms of host selectivity and key enzymes in the viral replication pathway. The recent crystallization of the H5N1 HA protein and NA enzyme offer new chances for drug discovery and translational medicine research. This project plays an integrative role in NBCR research and development, as well as opportunities for collaboration with researchers worldwide. We'll develop comprehensive solutions to the use of Relaxed Complex method and Molecular Dynamics in drug development, from preparation of protein structures, to selection of MD snapshots, to simulations of mutations using molecular modeling techniques. The MD techniques will also be developed to perform rescoring of docking experiments to refine the selection of top hits from virtual screening experiments using AutoDock and hierarchical screening procedures. The large computational requirements for these studies demand the use of supercomputers such as the BlueGene, as well as distributed resources such as the Open Science Grid, TeraGrid and community resources such as the World Community Grid. The resulting software through the encapsulation of these new algorithms will be of greater use to a wide range of diseases and mechanistic studies of protein ligand interactions.