TR&D Project 4. The Imaging Stage: Multiscale Spatiotemporal Modeling of Macromolecular Systems in Cellular Neighborhoods

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• 批准号: 10401763
• 负责人: ANDREJ SALI
• 金额: $ 17.44万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401763
• 关键词: ATP-Binding Cassette Transporters; Base Composition; Biogenesis; Biological Models; Chemicals; Complement; Complex; Cryo-electron tomography; Cryoelectron Microscopy; Data; Data Set; Electron Microscopy; Entropy; Free Energy; Gaussian model; Genetic Transcription; Image; Kinetics; Macromolecular Complexes; Maps; Methods; Microscope; Microscopy; Modeling; Molecular; Molecular Structure; Neighborhoods; Nuclear Pore Complex; Optics; Process; Proteins; Research; Resolution; Sampling; Spectrum Analysis; Statistical Data Interpretation; Structural Models; Structure; System; Time; Uncertainty; Validation; base; biological systems; crosslink; density; experimental study; improved; interest; macromolecular assembly; method development; microscopic imaging; novel strategies; open source; particle; peroxisome; restraint; satisfaction; simulation; single-molecule FRET; spatiotemporal; spindle pole body; stereochemistry; stoichiometry; theories

PROJECT SUMMARY TR&D Project 4. The Modeling Stage: Multiscale Spatiotemporal Modeling of Macromolecular Systems in Cellular Neighborhoods Here, we are concerned with the modeling of (i) static structures of large macromolecular machines and (ii) dynamic processes involving these machines. The accuracy, precision, and completeness of these models can in principle be improved by using all available information (ie, integrative modeling), including from various experiments, physical theories, statistical analyses, and prior models. We will improve several aspects of integrative modeling, tuning these improvements to the biological systems and data described in TR&Ds, DBPs, and C&SPs, and then implementing them in our open-source Integrative Modeling Platform (IMP) package. To improve integrative modeling of structures of macromolecular complexes, we will: (i) develop integrative modeling relying on near-atomic resolution cryo-electron microscopy density maps; (ii) develop explicit atomic- resolution representation of chemical cross-links; (iii) develop a scoring function for integrative modeling of related complexes from multiple species; and (iv) develop a sensitive Bayesian scoring function for assessing a model against cryo-EM single particle images. To improve integrative modeling of dynamics of macromolecular systems, we will: (i) estimate kinetic rate constants for changes in structure and composition based on time- dependent cryo-EM images; and (ii) develop integrative modeling of long macromolecular processes by satisfaction of spatiotemporal data. Finally, we will also leverage our method development efforts by supporting other developers and users of IMP.

项目概要 TR&D项目4.建模阶段：大分子系统的多尺度时空建模 在蜂窝小区 在这里，我们关注的是（i）大型高分子机器的静态结构和（ii）的建模 涉及这些机器的动态过程。这些模型的准确性、精密度和完整性可以 原则上可以通过使用所有可用的信息（即综合建模）来改进，包括来自各种 实验、物理理论、统计分析和先前模型。我们将从几个方面进行改进 综合建模，将这些改进调整到 TR&D、DBP 中描述的生物系统和数据， 和 C&SP，然后在我们的开源集成建模平台 (IMP) 包中实现它们。到 改进大分子复合物结构的综合建模，我们将：（i）开发综合模型 基于近原子分辨率冷冻电子显微镜密度图的建模； (ii) 开发明确的原子 化学交联的分辨率表示； (iii) 开发综合建模的评分函数 来自多个物种的相关复合物； (iv) 开发一个敏感的贝叶斯评分函数来评估 针对冷冻电镜单粒子图像的模型。改进大分子动力学的综合建模 系统，我们将：（i）根据时间估计结构和成分变化的动力学速率常数 相关冷冻电镜图像； (ii) 开发长大分子过程的综合模型 时空数据满意度。最后，我们还将通过支持来利用我们的方法开发工作 IMP 的其他开发者和用户。