Multi-Resolution Docking Methods for Electron Microscopy

描述（由申请人提供）：大分子组装体是生物细胞的基本功能单元;它们为药物设计提供了靶点，因为它们的结构缺陷通常与健康问题有关。拟议的研究的总体目标是电子显微镜（EM）的计算定量拟合工具的发展，结合联合收割机的低分辨率图像重建的大型组件与互补的原子分辨率数据的单个亚基的常规测定的大规模结构的生物分子机器。要解决的关键问题包括：（一）如何能够准确地识别几何特征的结构数据，可以作为锚点的刚体和灵活的匹配？(ii)在匹配算法的设计中，如何考虑分子结构的构象变异性（异质性）？(iii)基于经典互相关系数的六维刚体搜索对于结构的实时对准是否足够有效？(iv)如何以免费开源软件包的形式向全球用户社区传播我们的创新？我们将使用减少模式匹配和神经网络的密度图的粗略估计，并确定合适的地标多分辨率数据的注册模型。作为这种间接方法的补充，将使用并行计算架构（为了计算速度）在倒易空间中进行穷举刚体搜索，部分基于比较数据集的相关性（为了准确性）。该项目支持的计算实验室将广泛用于软件开发和EM中的拟合应用。合作的努力将包括细化肌球蛋白马达，GroEL伴侣蛋白，RNA聚合酶组件。这些发展的结果将是新的计算机代码，提供了一个可理解的和灵活的方法来多分辨率建模的大型组件。算法和方法的发展将通过Situs对接包所采用的既定互联网机制免费分发。

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.