Group-Theoretic Methods in Protein Structure Determina-n

蛋白质结构测定中的群论方法

• 批准号: 7845819
• 负责人: Gregory Chirikjian
• 金额: $ 15.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845819
• 关键词: Address; Agreement; Algorithms; Applications Grants; Budgets; Characteristics; Computer Simulation; Correlation Studies; Data; Databases; Evaluation; Funding; Generations; Goals; Grant; Grant Review; Helix-Loop-Helix Motifs; Heme; Human; Individual; Laboratories; Length; Methodology; Methods; Modality; Molecular Conformation; Motion; Neisseria meningitidis; Oxygenases; Postdoctoral Fellow; Price; Proteins; Recovery; Reporting; Residual state; Robotics; Sampling; Structure; Students; Techniques; Tertiary Protein Structure; Testing; United States National Institutes of Health; Wages; base; cost; data mining; data modeling; flexibility; improved; kinematics; member; protein structure; public health relevance; statistics

DESCRIPTION (provided by applicant): Notice: NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Applications SUMMARY STATEMENT "Group Theoretic Methods in Protein Structure Determination" The emphasis of this supplemental application is to analyze the statistics of ensembles of conformations of flexible proteins. That is, whereas the original grant focuses on new algorithms for determining protein structures from a variety of experimental modalities, the goal of this supplemental application is to quantify the variability of conformations represented in structural data. One of the most obvious examples of this is in NMR, where ensembles of conformations are often reported rather than an individual structure. The following specific aims to be addressed in this highly focused nine-month effort add to the original three specific aims: Specific Aim 4: Efficient Generation of Ensemble Statistics of Flexible Loop Conformations. In this specific aim, new methods from the field of robotic manipulator kinematics based on the concept of convolution and covariance propagation on the group of rigid-body motions will be used to generate ensemble statistics of candidate loop conformations without explicitly sampling conformational space. By circumventing the exponential price associated with traditional sampling techniques, we anticipate making a qualitative difference in the way protein-loop conformations are analyzed, not just a quantitative difference in particular computations. As a concrete test case, we will apply this methodology to the structure determination of human Ube2g2. Specific Aim 5: Evaluation of the Biasing Effects of Loops in the Assembly of Secondary Structures. In this specific aim we will study the correlation between loop length/composition and the special geometric characteristics of the resulting secondary structure interactions. We will begin by considering the helix-helix interaction in the helix-loop-helix motif and the relationship between helix interaction parameters and the parameters defining the loop. In other words, we will examine geometric characteristics such as crossing angle and where along the helix lengths the helices contact each other that depends on loop parameters. This is a purely in- silico objective, which will involve mining data from the Protein Data Bank. Specific Aim 6: Characterizing the Tertiary Ensemble. We will evaluate the following hypothesis: Protein tertiary structures do not always exist as single conformations, and enumeration of members of the 'tertiary ensemble' will better match experimental data than models in which a single conformation is assumed. We will test this hypothesis by validating tertiary ensembles against NMR residual dipolar couplings. In particular, we propose to utilize Neisseria meningitidis Heme Oxygenase (nmHO) as a test case of our ability to generate tertiary ensembles which maintain, or even improve, agreement with NMR data such as RDCs. Since the original grant is currently in no-cost extension, and almost all of the funds have been spent, this competitive renewal will provide an avenue for the continued funding of PI/co-PI salaries, a postdoc, and two students for a nine-month period. This, together with the proposed budget for laboratory supplies, constitutes the proposed request. PUBLIC HEALTH RELEVANCE: The emphasis of this supplemental application is to analyze the statistics of ensembles of conformations of flexible proteins. That is, whereas the original grant focuses on new algorithms for determining protein structures from a variety of experimental modalities, the goal of this supplemental application is to quantify the variability of conformations represented in structural data.

描述（由申请人提供）：通知：NOT-OD-09-058，NIH 宣布恢复法案资金可用于竞争性应用摘要声明“蛋白质结构测定中的群论方法”本补充申请的重点是分析柔性蛋白质构象集合的统计数据。也就是说，虽然最初的资助重点是通过各种实验方式确定蛋白质结构的新算法，但该补充申请的目标是量化结构数据中表示的构象的变异性。最明显的例子之一是核磁共振，其中经常报告构象的整体而不是单个结构。在这项高度集中的九个月努力中，除了最初的三个具体目标之外，还需要解决以下具体目标： 具体目标 4：有效生成灵活环构象的集成统计数据。在这个特定目标中，基于刚体运动组的卷积和协方差传播概念的机器人操纵器运动学领域的新方法将用于生成候选循环构象的集合统计，而无需显式采样构象空间。通过规避与传统采样技术相关的指数价格，我们预计蛋白质环构象的分析方式会产生质的差异，而不仅仅是特定计算中的量的差异。作为一个具体的测试案例，我们将将该方法应用于人类Ube2g2的结构测定。具体目标 5：评估二级结构组装中循环的偏置效应。在这个具体目标中，我们将研究环长度/组成与所产生的二级结构相互作用的特殊几何特征之间的相关性。我们将首先考虑螺旋-环-螺旋基序中的螺旋-螺旋相互作用以及螺旋相互作用参数与定义环的参数之间的关系。换句话说，我们将检查几何特征，例如交叉角以及螺旋沿螺旋长度相互接触的位置，这取决于环参数。这是一个纯粹的计算机目标，涉及从蛋白质数据库中挖掘数据。具体目标 6：表征第三系整体。我们将评估以下假设：蛋白质三级结构并不总是以单一构象存在，并且“三级整体”成员的枚举将比假设单一构象的模型更好地匹配实验数据。我们将通过针对 NMR 残余偶极耦合验证三级系综来检验这一假设。特别是，我们建议利用脑膜炎奈瑟氏菌血红素加氧酶（nmH2O）作为我们生成三级集合的能力的测试用例，这些集合保持甚至改进与 NMR 数据（例如 RDC）的一致性。由于最初的资助金目前处于免费延期状态，并且几乎所有资金都已用完，因此这次竞争性续签将为 PI/co-PI 工资、一名博士后和两名学生提供为期九个月的持续资助的途径。这与实验室用品的拟议预算一起构成了拟议的要求。 公共健康相关性：该补充应用的重点是分析柔性蛋白质构象集合的统计数据。也就是说，虽然最初的资助重点是通过各种实验方式确定蛋白质结构的新算法，但该补充申请的目标是量化结构数据中表示的构象的变异性。

项目成果

HNCO-based measurement of one-bond amide 15N-1H couplings with optimized precision.

• DOI: 10.1007/s10858-009-9391-2
• 发表时间: 2010-02
• 期刊: Journal of biomolecular NMR
• 影响因子: 2.7
• 作者: Arbogast L;Majumdar A;Tolman JR
• 通讯作者: Tolman JR

A Unified Approach to Conformational Statistics of Classical Polymer and Polypeptide Models.

经典聚合物和多肽模型构象统计的统一方法。

• DOI: 10.1016/j.polymer.2005.09.012
• 发表时间: 2005
• 期刊: Polymer
• 影响因子: 4.6
• 作者: Kim,JinSeob;Chirikjian,GregoryS
• 通讯作者: Chirikjian,GregoryS

Torsional random walk statistics on lattices using convolution on crystallographic motion groups.

使用晶体运动群卷积的晶格扭转随机游走统计。

• DOI: 10.1016/j.polymer.2007.01.066
• 发表时间: 2007
• 期刊: Polymer
• 影响因子: 4.6
• 作者: Skliros,Aris;Chirikjian,GregoryS
• 通讯作者: Chirikjian,GregoryS

Accurate image rotation using hermite expansions.

使用 Hermite 扩展进行精确的图像旋转。

• DOI: 10.1109/tip.2009.2024582
• 发表时间: 2009
• 期刊: IEEE transactions on image processing : a publication of the IEEE Signal Processing Society
• 作者: Park,Wooram;Leibon,Gregory;Rockmore,DanielN;Chirikjian,GregoryS
• 通讯作者: Chirikjian,GregoryS

Interconversion between truncated Cartesian and polar expansions of images.

图像的截断笛卡尔膨胀和极坐标膨胀之间的相互转换。

• DOI: 10.1109/tip.2007.899190
• 发表时间: 2007
• 期刊: IEEE transactions on image processing : a publication of the IEEE Signal Processing Society
• 作者: Park,Wooram;Chirikjian,GregoryS
• 通讯作者: Chirikjian,GregoryS