Ensemble Docking Interrogates Structural Determinants of Ligand-Protein Interactions

通过这一奖项，美国国家科学基金会化学部的生命过程化学项目支持范德比尔特大学的Jens Meeller博士开展的一项国际合作努力，为RosettaLigand分子建模项目开发一种新的、可能普遍适用的系综对接方法。这次合作的德国团队将由莱比锡大学的Annette Beck-Sickinger博士和Torsten Schoenefeld博士领导，并将得到DFG(Deutsche Forschungsgomeinschaft)的支持，并代表合作的试验方。将采取的系综对接方法包括同时对接多个配体，同时考虑将实验SAR(结构-活性关系)作为评分函数的一部分。合作小组选择了G蛋白偶联的7(螺旋)跨膜受体(GPCRs)家族和候选配体作为开发这一方法学的平台。德国合作团队将采取一种自然的产品启发方法来开发/结合这些受体的配体。鉴于蛋白质-膜受体相互作用在化学生物学中的重要性，拟议的研究旨在开发具有潜在广泛适用性的电子方法学。事实上，在这里的成功和向社区传播设想的RosettaEnSembleDock模块的可能性可以说是这一合作努力最重要的科学影响。GPCRs在生物学信号转导中的重要性怎么强调都不为过，因此建立这种计算算法的模型系统也具有相当重要的意义。该项目将提供跨学科和国际学生培训和交流，以及德国的蛋白质-配体结合实验小组与美国的计算模型/算法开发小组的协同互动。

With this award, the Chemistry of Life Processes Program in the Chemistry Division at NSF is supporting the work of Dr. Jens Meiler of Vanderbilt university on an international collaborative effort to develop a new and potentially generally useful ensemble docking method for the RosettaLigand molecular modeling program. The German team inthis collaboration will be led by Drs. Annette Beck-Sickinger and Torsten Schoenefeld at U. Leipzig and will be supported by the DFG (Deutsche Forschungsgemeinschaft), and represents the experimental side of the collaboration. The ensemble docking approach to be taken involves simultaneous docking of multiple ligands while considering experimental SAR (Structure-Activity Relationships) as part of the scoring function. The collaborative team has selected the family of G-protein-coupled 7-(helix) transmembrane receptors (GPCRs) and ligand candidates as a platform upon which to develop this methodology. The German partnering team will take a natural product-inspired approach to ligand development/binding assessment for these receptors. Given the importance of protein-membrane receptor interactions across chemical biology, the proposed research aims at developing in silico methodology with potentially broad applicability to the community. Indeed success here and the possibility for disseminating the envisioned RosettaEnsembleDock module to the community would constitute arguably the most important scientific broader impact of this collaborative effort. The importance of GPCRs in signal transduction in biology cannot be overstated and therefore the model system upon which this computational algorithm is being built is also of considerable significance. The project will provide for interdisciplinary and international student training and exchange, and for the synergistic interaction of experimental protein-ligand binding team in Germany with a computational modeling/algorithm development team in the United States.