Study of Biological Evolution of Structure and Function in Proteins

蛋白质结构和功能的生物进化研究

• 批准号: 8624697
• 负责人: EUGENE I SHAKHNOVICH
• 金额: $ 53.98万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624697
• 关键词: Address; Adverse effects; Algorithms; Animal Model; Bacteria; Base Sequence; Biological; Biophysics; Budgets; Cell division; Cells; Chemicals; Collaborations; Computing Methodologies; Cytoplasm; Data; Death Rate; Dependence; Development; Ecology; Environment; Equilibrium; Escherichia coli; Essential Genes; Evolution; Exhibits; Feedback; Foundations; Genes; Genomics; Genotype; Goals; Homology Modeling; Infection; Intercistronic Region; Life; Life Style; Measurement; Medical; Medicine; Metabolic Pathway; Methods; Microscopic; Modeling; Molecular; Molecular Evolution; Mutation; Nature; Organism; Paper; Pathway interactions; Pattern; Phenotype; Phylogeny; Plant Roots; Population; Population Genetics; Population Sizes; Positioning Attribute; Progress Reports; Property; Proteins; Proteome; Publishing; Research; Resolution; Sequence Alignment; Set protein; Signal Transduction; Structure; Testing; Treatment Protocols; Work; bacterial resistance; base; biophysical properties; fighting; fitness; genome sequencing; improved; insight; multi-scale modeling; novel; practical application; protein distribution; protein function; protein protein interaction; protein structure function; reconstruction; research study; simulation; theories; tool; trait

DESCRIPTION (provided by applicant): The overarching goal of the proposed research is to study evolution of structure, Biophysical properties and function of proteins in the context of Darwinian evolution of their carrier organisms. In the past budget period we significantly advanced towards that goal by introducing rich, powerful yet tractable multiscale models of protein evolution which derive organismal fitness from genomic sequences via intuitive yet realistic Genotype- Phenotype relationships which relate biophysical and functional properties of proteins to important phenotypic traits such cell division. Here we will further develop this approach by adding more realism to the models including treatment of proteins in sequence-based multiscale model at atomic resolution, prototypical E.coli glycolytic pathway, effect of misfolding on fitness and effect of protein abundances. Specific problems that will be addressed include the effect of ecology of the population on key Biophysical properties of proteins such as distribution of their stabilities, abundances and strengths of protein-protein interactions in the proteome; reconstruction of ancestor sequences and molecular phylogenies from genomics data within physically realistic models, relationship between protein stability, abundance in cytoplasm, and rate of their evolution. Predictions and insights from multiscale models will be vigorously tested against high-throughput Bioinfiomatic analyses and experiment. Experimental studies proposed here include measurements of stabilities of statistically representative sets of proteins in several proteomes, of bacteria having various ecological parameters (e.g population sizes and/or mutation rates). Successful completion of these studies will advance our ability to extract functionally relevant signals from genomic sequences by putting their analysis on firm evolutionary and Biophysical ground.

描述（由申请人提供）：拟议研究的总体目标是在其载体生物体的达尔文进化背景下研究蛋白质的结构、生物物理特性和功能的进化。在过去的预算期内，我们通过引入丰富、强大且易于处理的蛋白质进化多尺度模型，显着推进了这一目标，该模型通过直观而现实的基因型-表型关系，从基因组序列中获得有机体适应性，该关系将蛋白质的生物物理和功能特性与重要的表型特征联系起来这样的细胞分裂。在这里，我们将通过为模型添加更多真实性来进一步开发这种方法，包括在基于序列的多尺度模型中以原子分辨率处理蛋白质、原型大肠杆菌糖酵解途径、错误折叠对适应性的影响以及蛋白质丰度的影响。将解决的具体问题包括种群生态对蛋白质关键生物物理特性的影响，例如蛋白质组中蛋白质-蛋白质相互作用的稳定性、丰度和强度的分布；根据物理真实模型中的基因组数据重建祖先序列和分子系统发育、蛋白质稳定性、细胞质丰度及其进化速率之间的关系。多尺度模型的预测和见解将根据高通量生物信息学分析和实验进行严格测试。这里提出的实验研究包括测量具有各种生态参数（例如群体大小和/或突变率）的细菌的几种蛋白质组中具有统计代表性的蛋白质组的稳定性。这些研究的成功完成将提高我们从基因组序列中提取功能相关信号的能力，将其分析置于坚实的进化和生物物理学基础上。