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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 由于禽流感大流行的威胁迫在眉睫，现有的抗病毒抑制剂可能由于流感病毒的高突变率而效力有限。虽然制药和生物技术行业在开发新疫苗和新干预手段方面投入了大量资金，但需要进行更多的基础研究，以了解禽流感传染生命周期的作用机制，特别是在宿主选择性和病毒复制途径中的关键酶方面。近年来H5 N1病毒HA蛋白和NA酶的结晶为药物发现和转化医学研究提供了新的契机。 该项目在NBCR的研究和开发中发挥着综合作用，并提供了与全球研究人员合作的机会。我们将开发全面的解决方案，在药物开发中使用松弛复合物方法和分子动力学，从蛋白质结构的制备，到MD快照的选择，再到使用分子建模技术模拟突变。还将开发MD技术，以执行对接实验的重新评分，从而使用AutoDock和分层筛选程序从虚拟筛选实验中完善最佳命中的选择。这些研究的大量计算需求需要使用超级计算机，如BlueGene，以及分布式资源，如开放科学网格，TeraGrid和社区资源，如World Community Grid。通过封装这些新的算法所得到的软件将有更大的用途，以广泛的疾病和蛋白质配体相互作用的机制研究。

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.