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.

说明(由申请人提供)：通知：NOT-OD-09-058，NIH宣布恢复法资金可用于竞争应用摘要声明“蛋白质结构确定中的群论方法”本补充申请的重点是分析柔性蛋白质构象的系综统计。也就是说，虽然最初的拨款侧重于从各种实验模式确定蛋白质结构的新算法，但这种补充应用的目标是量化结构数据中表示的构象的可变性。这方面最明显的例子之一是核磁共振，在核磁共振中，通常报告的是构象的系综，而不是单个结构。在这项为期9个月的高度集中的努力中，以下具体目标是在最初的三个具体目标的基础上增加的：具体目标4：灵活环构象集合统计的有效生成。在这一特定的目标下，机器人运动学领域基于刚体运动组卷积和协方差传播概念的新方法将被用来生成候选环状构象的集成统计，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，我们预计将在分析蛋白质环构象的方式上产生质的不同，而不仅仅是特定计算中的定量差异。作为一个具体的测试案例，我们将把该方法应用于人类UBE2G2的结构确定。具体目标5：评估二级结构组装中环的偏置效应。在这个特定的目标中，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。我们将从考虑螺旋-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和定义环的参数之间的关系开始。换句话说，我们将检查取决于环参数的几何特征，例如交叉角度以及螺旋长度上螺旋相互接触的位置。这是一个纯粹的计算机内目标，它将涉及从蛋白质数据库中挖掘数据。具体目标6：第三代乐团的特征。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，与假设单一构象的模型相比，对“三级系综”成员的枚举将更好地与实验数据匹配。我们将通过验证三级系综与核磁共振剩余偶极耦合来验证这一假设。特别是，我们建议利用脑膜炎奈瑟菌的血红素加氧酶(NmHO)作为测试案例，以测试我们产生第三级集成的能力，这些集成保持甚至改善与RDC等核磁共振数据的一致性。由于最初的补助金目前是免费延长的，而且几乎所有的资金都已经用完，这一竞争性续期将为在九个月期间继续资助PI/共同PI的薪金、一名博士后和两名学生提供资金。这与实验室用品拟议预算一起构成了拟议的请求。 公共卫生相关性：这一补充应用的重点是分析柔性蛋白质构象的系综的统计数据。也就是说，虽然最初的拨款侧重于从各种实验模式确定蛋白质结构的新算法，但这种补充应用的目标是量化结构数据中表示的构象的可变性。

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