Multi-Resolution Docking Methods for Electron Microscopy

电子显微镜的多分辨率对接方法

• 批准号: 6874858
• 负责人: WILLY R WRIGGERS
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874858
• 关键词: actins; bioimaging /biomedical imaging; computer program /software; computer simulation; computer system design /evaluation; conformation; electron microscopy; macromolecule; method development; microfilaments; microtubule associated protein; microtubules; molecular dynamics; protein structure; ribosomes; technology /technique development; transcription factor; translation factor

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.

描述（由申请人提供）：大分子组装体是基本的 生物细胞的功能单位；它们为药物设计提供了目标，例如 其架构的缺陷常常与健康问题有关。 拟议研究的总体目标是发展计算 用于电子显微镜 (EM) 的定量拟合工具结合了 具有互补性的大型组件的低分辨率图像重建 单个亚基的原子分辨率数据，用于常规测定 大规模的聚集体结构。需要解决的关键问题包括： (i) 如何准确地将实验几何约束包含在 单分子对接？ (ii) EM 图中是否存在这些特征 充分定义的程序集可实现快速、粗粒度的注册 基于密度估计的模板结构？ (iii) 是一个六维空间 在实验数据限制下，刚体搜索高效且稳健，例如 作为比较结构中未考虑的部分？我们将使用拓扑 表示用于粗略估计密度图的神经网络以及 确定适合多分辨率数据配准的地标。 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倒易空间中执行（对于 计算速度）部分基于比较数据集的梯度 （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 中的拟合应用程序。 合作努力将包括细化肌动蛋白丝和 微管及其与马达和因素相互作用的研究 促进它们的拆卸，以及对伸长因子的建模 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一种易于理解且灵活的方法 大型装配体。算法和方法论的发展将是 通过已建立的基于互联网的机制自由分发 用于 Situs 对接包。