Multi-Resolution Docking Methods for Electron Microscopy

描述（由申请人提供）：大分子组件是生物细胞的基本功能单元；它们为药物设计提供了目标，因为它们的结构缺陷经常与健康问题有关。拟议研究的总体目标是开发用于电子显微镜（EM）的计算定量拟合工具，该工具将大型组件的低分辨率图像重建与单个亚基的互补原子分辨率数据相结合，用于常规确定生物分子机器的大规模结构。需要解决的关键问题包括：(i)如何准确识别结构数据的几何特征，这些特征可以作为刚体和柔性匹配的锚点？（ii）如何在匹配算法的设计中考虑到分子结构的构象变异性（异质性）？（iii）基于经典相互关联系数的六维刚体搜索是否足以有效地实现结构的实时对准？（iv）如何以免费的开放源码软件包的形式将我们的创新成果最好地传播给全球用户社区？我们将使用来自模式匹配和神经网络的简化模型对密度图进行粗略估计，并确定适合多分辨率数据注册的地标。作为这种间接方法的补充，将使用并行计算架构（计算速度）在互反空间中执行详尽的刚体搜索，该架构部分基于比较数据集的相关性（准确性）。由该项目支持的计算实验室将广泛用于软件开发和EM的适配应用。合作努力将包括改进肌凝蛋白马达、GroEL伴侣蛋白和RNA聚合酶组装。这些发展的结果将是新的计算机代码，为大型组件的多分辨率建模提供可理解和灵活的方法。算法和方法的发展将通过Situs对接包所采用的基于互联网的机制免费分发。

DESCRIPTION (provided by applicant): Macromolecular assemblies are the basic functional units of biological cells; they furnish targets for drug design, as deficiencies in their architecture are frequently linked to health problems. The overall goal of the proposed research is the development of computational quantitative fitting tools for electron microscopy (EM) that combine low-resolution image reconstructions of large assemblies with complementary atomic resolution data of individual subunits for routine determination of the large-scale structure of biomolecular machines. Key questions to be addressed include: (i) How can one accurately identify geometric features of structural data that may serve as anchor points for rigid body and flexible matching? (ii) How can one take into account the conformational variability (heterogeneity) of molecular structures in the design of matching algorithms? (iii) Is a six-dimensional rigid-body search based on the classical cross-correlation coefficient sufficiently efficient for a real-time alignment of structures? (iv) How can one best disseminate our innovations to the global user community in the form of free open source software packages? We will use reduced models from pattern matching and neural networks for a coarse estimation of density maps and for determining suitable landmarks for the registration of multi-resolution data. Complementary to this indirect approach an exhaustive rigid body search will be performed in reciprocal space using parallel computing architectures (for computational speed) based in part on the correlation of the compared data sets (for accuracy). A computational laboratory supported by this project will be used extensively for software development and for fitting applications in EM. Collaborative efforts will include the refinement of myosin motors, GroEL chaperonins, and RNA polymerase assemblies. The results of these developments will be new computer codes that provide a comprehensible and flexible approach to the multi-resolution modeling of large assemblies. The algorithmic and methodological developments will be distributed freely through the established internet-based mechanisms employed for the Situs docking package.