Multi-Resolution Docking Methods for Electron Microscopy

描述（由申请人提供）：大分子组装是基本的 生物细胞的功能单位;它们为药物设计提供目标，如 其建筑缺陷通常与健康问题有关。 所提出的研究的总体目标是发展计算 用于电子显微镜（EM）的定量拟合工具，其结合联合收割机 具有互补性的大型组件的低分辨率图像重建 用于常规测定的单个亚单位的原子分辨率数据 大规模的聚集体结构。需要解决的关键问题包括：㈠ 如何准确地将实验几何约束包括在 单分子对接(ii)电磁图中的特征是否 为快速粗粒度配准充分定义的组件 基于密度估计的模板结构？(iii)是一个六维的 刚体搜索在实验数据限制下有效且鲁棒， 作为比较结构中的未知部分吗我们将使用拓扑学 表示用于密度图的粗略估计和用于 - 确定用于多分辨率数据的配准的合适界标。 作为这种间接方法的补充，将进行详尽的刚体搜索， 使用并行计算架构在倒易空间中执行（对于 计算速度），部分地基于所比较的数据集的梯度 (for准确度）。由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。 合作的努力将包括完善肌动蛋白丝， 微管，以及它们与马达和因子的相互作用的研究 促进他们的拆卸，和建模的伸长率因素对 核糖体这些发展的结果将是新的计算机代码， 为多分辨率建模提供了一种可理解和灵活的方法 大型集会。算法和方法的发展将是 通过所采用的既定因特网机制自由分发 用于Situs对接包

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 aggregates. Key questions to be addressed include: (i) How can one accurately include experimental geometric constraints in the docking of single molecules? (ii) Are the features present in EM maps of assemblies sufficiently well-defined for a rapid, coarse-grained registration of template structures based on density estimation? (iii) Is a six-dimensional rigid-body search efficient and robust under experimental data limitations such as unaccounted parts in the compared structures? We will use topology representing 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 gradient 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 actin filaments and microtubules, and the study of their interactions with motors and with factors promoting their disassembly, and the modeling of elongation factors on the ribosome. 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.