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）：拟议的研究的总体目标是在达尔文载体生物的发展中研究结构，生物物理特性和蛋白质功能的演变。在过去的预算期内，我们通过引入蛋白质演化的丰富，强大但可触及的多尺度模型来朝着该目标迈进，从而通过直觉但逼真的基因型 - 表型关系从基因组序列中得出有机体适应性，从而将蛋白质的生物物理和功能特性与蛋白质的生物物理和功能性关系相关联。在这里，我们将通过在原子分辨率，原型型大肠杆菌糖酵解途径上添加更多的模型，包括对蛋白质的处理，包括对蛋白质的处理，进一步开发这种方法，包括对蛋白质折叠的影响以及蛋白质丰度的影响的影响。将要解决的具体问题包括人群生态学对蛋白质的关键生物物理特性的影响，例如其稳定性的分布，蛋白质蛋白质相互作用在蛋白质组中的分布；从物理逼真的模型中基因组数据，蛋白质稳定性，细胞质中丰度之间的关系及其进化速率之间的基因组数据中的祖先序列和分子系统发育的重建。多尺度模型的预测和见解将对高通量生物infiomatic分析和实验进行大力测试。这里提出的实验研究包括测量几种蛋白质组中统计代表性蛋白质集的稳定性，具有各种生态参数的细菌（例如种群大小和/或突变率）。这些研究的成功完成将提高我们通过将分析放在牢固的进化和生物物理基础上，从而提高我们从基因组序列中提取功能相关信号的能力。