Grid-enabled Integration of Experimental Data and Simulations for Flexible Protein Docking

圣母大学获得了一笔赠款，用于实现实验数据和模拟的网格集成，以实现灵活的蛋白质对接。阐明蛋白质与配体或其他蛋白质的相互作用对于基于结构的药物设计和蛋白质组学是至关重要的。与将蛋白质视为刚性构象相比，对蛋白质的柔韧性进行建模实质上更准确(也更昂贵)。目前的方法有效地适应了侧链运动。在这个奖项中，这一方法被扩展到使用实验数据和多尺度模拟来适应更大的运动。通过将对接协议与构象采样和分析相结合，对接效率也将得到提高。这些方法将在HIV-1蛋白酶、HIV-1整合酶和二氢叶酸还原酶(DHFR)上得到验证，这些酶的结构和动力学数据都很丰富。推测的相互作用将通过核磁共振实验得到验证。这项研究将产生基于网格的工具和一个数据库，用于分子模拟和对接，可供研究界使用。数据库技术的一个新方面将是对网格上存储的可靠性和可用性进行有效管理。将在学生和调查人员之间进行跨学科培训和合作。

The University of Notre Dame is awarded a grant to pursue grid-enabled integration of experimental data and simulations for flexible protein docking. The elucidation of interactions of a protein with ligands or other proteins is crucial for structure-based drug design and proteomics. Modeling the flexibility of proteins is substantially more accurate (and more expensive) than considering the protein as a rigid conformation. Current methodology effectively accommodates side chain motions. In this award this methodology is extended to accommodate larger motions using experimental data and multiscale simulations. The efficiency of docking will also be improved through integration of docking protocols with conformational sampling and analysis. These methods will be validated on HIV-1 protease, HIV-1 integrase, and Dihydrofolate Reductase (DHFR), for which abundant structural and dynamical data exists. Putative interactions will be validated through NMR experiments. This research will produce grid-based tools and a database for molecular simulations and docking accessible to the research community. A novel aspect of the database technology will be the efficient management of reliability and availability of storage on the grid. There will be interdisciplinary training and collaboration among students and the investigators.