Modeling evolution of functional context in proteins

蛋白质功能背景的进化建模

基本信息

  • 批准号:
    8245205
  • 负责人:
  • 金额:
    $ 32.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-03-01 至 2014-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): As proteins accumulate change and diverge over time, they must continue to satisfy the structural and energetic constraints that enable them to function properly. Because of this, the diversity of protein sequences available from living organisms represents a wealth of data on the relationships between protein sequence, structure, and function. Extracting insights from these data, however, remains a challenge. In principle, the optimal approach to decoding functional information in protein sequence biodiversity is to use parametric statistical inference with realistic phylogeny-based models. Historically, this approach has been limited by the amount of sequence data available, and by the difficulty and prohibitive computational complexity of the probability calculations needed. Sequence biodiversity has become much more readily available in the post-genomic era, and yet despite important advances by a few groups, the vast majority of research making use of comparative sequence information has depended on models with numerous convenience-motivated assumptions that ignore important biological effects such as the variation of structural and functional contexts across residues in a protein, and over time. These simplifications prevent the full potential of comparative genomic data from being brought to bear on the role of genetic variation in health and disease, and thus may pose significant roadblocks to biological and biomedical discovery. Here, it is proposed to take advantage of recently developed methods, which we have designed to remedy this situation by eliminating the need for potentially misleading model over-simplifications. We will use these methods to model complex context-dependent variation in evolutionary patterns across positions in proteins, and to model how these patterns change over time and in response to external influences. The evolutionary patterns at different positions will be related to known structural and energetic features and, based on these analyses, new models will be developed that directly incorporate bona fide biological effects. Because of our algorithmic advances, these models can be built to more accurately reflect the true complexity of interdependent sequence, structural and functional effects on evolutionary processes, yielding unparalleled power to detect subtle but meaningful effects, to provide better predictive capabilities, and to more precisely characterize the causes and consequences of protein evolution. The proposed research is broadly important for human health because of the central role that protein function and dysfunction play in the mechanisms and etiology of a vast majority of human diseases and health disorders. Thus, a better understanding of the relationship between sequence variation, structure, and function will yield better prediction of the effects of human mutations, greater understanding of protein function and its role in human biology, improved rational design of novel proteins that might be used to improve human health, and potentially more accurate structure-based drug design. The proposed research will focus on modeling proteins encoded in complete vertebrate mitochondrial genomes, taking advantage of the uniquely dense sequence sampling available across diverse vertebrate species. We will pay detailed attention to primate, including human, mitochondrial genomes, so that our research will provide specific insight into how key oxidative phosphorylation proteins function, and how mutations in these genes lead to human diseases by disrupting structure and function. Given the central importance of the mitochondrion to aging, disease (e.g., diabetes, Parkinson's, Alzheimer's, and other neurological diseases) and to cellular processes including apoptotic cell death, such insights may prove directly beneficial as a hypothesis-generating and testing platform for experimental, pharmacological, and translational research in several areas. By design, this project will pave the way for future research on nuclear genome datasets as their number and diversity increases.
描述(由申请人提供):随着时间的推移,蛋白质积累变化和分化,它们必须继续满足结构和能量限制,使它们能够正常工作。正因为如此,从活生物体中获得的蛋白质序列的多样性代表了蛋白质序列、结构和功能之间关系的丰富数据。然而,从这些数据中提取见解仍然是一个挑战。原则上,解码蛋白质序列生物多样性功能信息的最佳方法是使用基于现实系统发育模型的参数统计推断。从历史上看,这种方法受到可用序列数据的数量,以及所需概率计算的难度和令人望而却步的计算复杂性的限制。序列生物多样性在后基因组时代变得更加容易获得,然而,尽管少数研究小组取得了重要进展,但绝大多数利用比较序列信息的研究都依赖于具有许多便利动机假设的模型,这些假设忽略了重要的生物效应,例如蛋白质中残基之间结构和功能背景的变化,以及随时间的变化。这些简化使比较基因组数据的全部潜力无法用于研究遗传变异在健康和疾病中的作用,因此可能对生物学和生物医学的发现构成重大障碍。在这里,我们建议利用最近开发的方法,我们设计这些方法是为了消除对潜在的误导性模型过度简化的需要,从而纠正这种情况。我们将使用这些方法来模拟蛋白质中不同位置的进化模式中复杂的上下文依赖性变化,并模拟这些模式如何随时间和外部影响而变化。不同位置的进化模式将与已知的结构和能量特征有关,并在这些分析的基础上,将开发直接纳入真正生物效应的新模型。由于我们在算法上的进步,这些模型可以更准确地反映出相互依赖的序列、结构和功能对进化过程的影响的真正复杂性,从而产生无与伦比的能力来检测细微但有意义的影响,提供更好的预测能力,并更准确地描述蛋白质进化的原因和后果。由于蛋白质功能和功能障碍在绝大多数人类疾病和健康失调的机制和病因学中发挥着核心作用,因此拟议的研究对人类健康具有广泛的重要性。因此,更好地理解序列变异、结构和功能之间的关系将更好地预测人类突变的影响,更好地理解蛋白质功能及其在人类生物学中的作用,改进可用于改善人类健康的新型蛋白质的合理设计,并可能更准确地设计基于结构的药物。拟议的研究将侧重于模拟完整脊椎动物线粒体基因组中编码的蛋白质,利用不同脊椎动物物种之间独特的密集序列采样。我们将详细关注灵长类动物,包括人类,线粒体基因组,以便我们的研究将提供具体的见解,了解关键的氧化磷酸化蛋白如何发挥作用,以及这些基因的突变如何通过破坏结构和功能导致人类疾病。鉴于线粒体对衰老、疾病(如糖尿病、帕金森病、阿尔茨海默病和其他神经系统疾病)和细胞凋亡等细胞过程的核心重要性,这些见解可能被证明是直接有益的,可以作为几个领域的实验、药理学和转化研究的假设生成和测试平台。通过设计,该项目将为未来核基因组数据集的研究铺平道路,因为它们的数量和多样性都在增加。

项目成果

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DAVID D POLLOCK其他文献

DAVID D POLLOCK的其他文献

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{{ truncateString('DAVID D POLLOCK', 18)}}的其他基金

Genome-wide mutation models to decipher function
用于破译功能的全基因组突变模型
  • 批准号:
    8776584
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
Genome-wide mutation models to decipher function
用于破译功能的全基因组突变模型
  • 批准号:
    9005906
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
Genome-wide mutation models to decipher function
用于破译功能的全基因组突变模型
  • 批准号:
    8606470
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
Genome-wide mutation models to decipher function
用于破译功能的全基因组突变模型
  • 批准号:
    8454425
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
Genome-wide mutation models to decipher function
用于破译功能的全基因组突变模型
  • 批准号:
    8238861
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
Genome-wide mutation models to decipher function
用于破译功能的全基因组突变模型
  • 批准号:
    8803386
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
Modeling evolution of functional context in proteins
蛋白质功能背景的进化建模
  • 批准号:
    8143199
  • 财政年份:
    2009
  • 资助金额:
    $ 32.12万
  • 项目类别:
Modeling evolution of functional context in proteins
蛋白质功能背景的进化建模
  • 批准号:
    9262235
  • 财政年份:
    2009
  • 资助金额:
    $ 32.12万
  • 项目类别:
Modeling evolution of functional context in proteins
蛋白质功能背景的进化建模
  • 批准号:
    7767710
  • 财政年份:
    2009
  • 资助金额:
    $ 32.12万
  • 项目类别:
Modeling evolution of functional context in proteins
蛋白质功能背景的进化建模
  • 批准号:
    8055568
  • 财政年份:
    2009
  • 资助金额:
    $ 32.12万
  • 项目类别:

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