Information Fusion in Biomolecular Structure and Motion Determination

生物分子结构和运动测定中的信息融合

• 批准号: 9059739
• 负责人: Gregory Chirikjian
• 金额: $ 36.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059739
• 关键词: Algorithms; Alzheimer' s Disease; Applications Grants; Architecture; Biological; Calculi; Collaborations; Complex; Computer software; Crystallography; Data; Data Set; Databases; Docking; Electron Microscopy; Family; Gated Ion Channel; Glutamate Receptor; Goals; Growth; Health; Individual; Information Sciences; Information Theory; Length; Letters; Ligands; Link; Macromolecular Complexes; Mainstreaming; Measurement; Methodology; Methods; Modality; Modeling; Molecular Conformation; Molecular Structure; Motion; Nature; Nucleosomes; Phase; Probability Theory; Procedures; Proteins; Resistance; Resolution; Roentgen Rays; Sampling; Signal Transduction; Source; Stroke; Structure; Students; System; Techniques; Testing; Validation; Work; base; biophysical techniques; cancer type; case-by-case basis; cell transformation; chromatin remodeling; computer code; data integration; density; experience; flexibility; improved; insight; interest; macromolecular assembly; mathematical methods; mathematical model; microscopic imaging; novel; prediction algorithm; programs; theories; tool; web page

DESCRIPTION (provided by applicant): Due to their inherently complex nature, the architecture and motions of large macromolecular assemblies composed of rigid constituents are typically dissected using multiple techniques. While often combined on a case-by-case basis, the lack of theoretical tools to optimally integrate information from different sources is a major barrier to generating a more complete/accurate understanding of important assemblies. Herein are proposed new information fusion algorithms for these assemblies, and their associated functional motions. This extends classical information science to the case of data on the Lie group of rigid-body motions. Utilizing data from electron microscopy (EM) and small-angle X-ray scattering (SAXS) measurements, these fusion algorithms will be applied to two large biomolecular assemblies: (1) the ionotropic glutamate receptor (iGluR), and (2) the Chd1-nucleosome complex. The specific aims are as follows: SA1: To develop new information-theoretic methods based on Euclidean-group calculus and probability theory to improve fitting of macromolecular structures into EM densities and SAXS envelopes, and to perform information fusion of compatible biophysical information from different modalities to produce greater understanding than when methods are taken individually. SA2: To apply mathematically optimized models of iGluR quaternary structure to uncover physiologically relevant conformational changes inaccessible to individual experimental methods. SA3: To develop and apply new mathematical models of flexibility and ensemble dynamics of the nucleosome alone and in complex with the Chd1 chromatin remodeler using EM and SAXS, leading to a better understanding of the structure-motion-function relationship. The results will validate novel algorithms for fusing information from different experimental approaches to determine conformational changes in macromolecular complexes. If successful, these algorithms will provide new mechanistic insights into the iGluR family of ligand-gated ion channels, implicated in stroke and Alzheimer's disease, and the Chd1 remodeler, which has been linked to several types of cancer.

描述(由申请人提供)：由于其固有的复杂性，由刚性组分组成的大分子组件的结构和运动通常使用多种技术来剖析。虽然经常在个案的基础上结合起来，但缺乏理论工具来最佳地整合来自不同来源的信息是一个问题 对重要装配进行更完整/准确的理解的主要障碍。在此，提出了新的信息融合算法，用于这些装配及其相关的功能运动。这将经典信息科学扩展到刚体运动的李群数据的情况。利用电子显微镜(EM)和小角X射线散射(SAXS)测量的数据，这些融合算法将被应用于两个大型生物分子组件：(1)离子型谷氨酸受体(IGluR)和(2)Chd1-核小体复合体。具体目标如下： SA1：发展新的基于欧几里德群微积分和概率论的信息论方法，以改进大分子结构与EM密度和SAXS包络的拟合，并对来自不同形式的兼容生物物理信息进行信息融合，以产生比单独采用方法更好的理解。 SA2：应用iGluR四元结构的数学优化模型，揭示个人实验方法无法获得的生理相关构象变化。 SA3：利用EM和SAXS开发和应用核小体单独和与Chd1染色质重构体复合的灵活性和整体动力学的新数学模型，从而更好地理解结构-运动-功能关系。这些结果将验证新的算法，用于融合来自不同实验方法的信息来确定大分子络合物的构象变化。如果成功，这些算法将为与中风和阿尔茨海默病有关的配体门控离子通道iGluR家族以及与几种类型癌症有关的Chd1重建器提供新的机械性见解。