Multi-Resolution Docking Methods for Electron Microscopy

描述(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靶标，如 它们架构上的缺陷往往与健康问题有关。 拟议研究的总体目标是发展计算 结合电子显微镜(EM)的定量拟合工具 具有互补结构的大型组件的低分辨率图像重建 用于常规测定的单个亚基的原子分辨率数据 集料的大规模结构。需要解决的主要问题包括：(I) 如何准确地将实验几何约束包含在 单分子对接？(Ii)电子地图上显示的特征 程序集定义得足够好，可以快速、粗粒度地注册 基于密度估计的模板结构？(Iii)是六维的 刚体搜索在实验数据限制下的高效和健壮 在比较的结构中作为下落不明的部分？我们将使用拓扑学 表示神经网络用于密度图的粗略估计和 为多分辨率数据配准确定合适的地标。 作为对这种间接方法的补充，详尽的刚体搜索将是 使用并行计算架构在互易空间中执行(用于 计算速度)部分地基于比较的数据集的梯度 (用于准确性)。由该项目支持的计算实验室将是 广泛用于软件开发和EM中的装配应用程序。 合作努力将包括提炼肌动蛋白细丝和 微管及其与发动机和因子相互作用的研究 促进它们的拆卸，并对伸长系数进行建模 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易于理解和灵活的方法 大型集会。算法和方法的发展将是 通过已建立的基于互联网的机制免费分发 西特斯对接包的费用。

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.