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: 7595225
• 负责人: EUGENE I SHAKHNOVICH
• 金额: $ 34.73万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595225
• 关键词: Address; Affect; Antibiotic Resistance; Autoimmunity; B-Lymphocytes; Biological; Biological Assay; Biological Models; Budgets; Cell Death; Cells; Cereals; Chemotaxis; Classification; Collaborations; DNA; Data; Disease; Event; Evolution; Family Sizes; Gene Family; Genes; Genetic; Genome; Genomics; Goals; Healed; Immune; Immune response; Immunity; Immunoglobulin Genes; Laws; Life; Microscopic; Modeling; Molecular; Molecular Evolution; Mutate; Mutation; Organism; Participant; Pathway interactions; Pattern; Phase; Phenotype; Phylogenetic Analysis; Phylogeny; Plasmids; Population Dynamics; Process; Property; Proteins; Proteome; Proteomics; RNA; Science; Structure; TF gene; Taxon; Temperature; Testing; Theoretical Studies; Time; Transcriptional Regulation; Variant; Viral; Virus; Work; base; essays; fitness; genetic regulatory protein; healing; mutant; particle; protein folding; protein function; protein protein interaction; protein structure; protein structure function; public health relevance; research study; response; simulation; theories; tool; transcription factor; transcription factor USF

DESCRIPTION (provided by applicant): Our ability to annotate and identify proteins and pathways that may be important targets to treat diseases is limited by the lack of systematic understanding of how proteins and functional modules evolved to carry out desired functions. While genomic projects accumulated vast amount of data on sequence, structure and function of proteins its systematic analysis is not possible in the absence of theory that relates their molecular properties to the functional constraints and evolutionary requirement on organisms that carry the genomes. This proposal aims to develop such theory where molecular evolution of proteins is studied in the context of Darwinian evolution of organisms that carry them. Theoretical and experimental research proposed here aims to address the following questions: 1) How did modern Universe of protein structures evolve in early biological evolution under the environmental and competitive constraints on organisms? Why some protein folds are overrepresented in many proteins and some are unique? 2) How do organisms adapt to extreme environmental conditions and how is that adaptation manifest in the compositional and structural repertoire of their genomes and proteomes? 3) How did new protein functions, such as error correction evolve in the process of conversion from RNA to DNA world? 4) How did participants in biological networks - transcription factors and upstream regions - co-evolve and how is it reflected in their phylogenetic profiles? 5) How did protein-protein interactions responsible for immune response evolve? 6) How does fitness landscape of an organism depend on molecular properties (such as stability) of proteins constituting it? These questions will be addressed using multi-tool approach that includes analytical theory, simulations of detailed microscopic evolutionary models using coarse grained and realistic representations of protein structures and experimental research that involves newly developed competitive fluorescent assays for wild type and mutant variant of E.coli as a model system. PUBLIC HEALTH RELEVANCE: This theoretical and experimental study aims to discover how protein structures and functions evolve in response to functional demands of organisms. It will help to identify biological modules that are responsible for diseases such as autoimmunity and immune deficiency and will help to formulate better anti-viral strategies.

描述（由申请人提供）：我们的注释能力和识别可能是治疗疾病的重要靶标的蛋白质和途径的能力受到对蛋白质和功能模块如何发展以执行所需功能的发展的限制。尽管基因组项目积累了大量的数据，但在没有将其分子特性与携带基因组的生物体的功能约束和进化要求的理论相关的理论的情况下，无法进行系统分析。该提议旨在发展这种理论，其中在携带它们的有机体进化的背景下研究了蛋白质的分子进化。这里提出的理论和实验研究旨在解决以下问题：1）现代蛋白质结构的现代宇宙如何在对生物的环境和竞争性限制下在早期生物学进化中进化？为什么在许多蛋白质中有些蛋白质褶皱过多，而有些则是独特的？ 2）生物体如何适应极端的环境条件，如何在其基因组和蛋白质组的组成和结构库中表现出来？ 3）新蛋白的功能（例如误差校正）如何在从RNA到DNA世界的转化过程中发展？ 4）生物网络中的参与者如何 - 转录因子和上游区域 - 共同进化，如何反映其系统发育特征？ 5）蛋白质 - 蛋白质相互作用如何发展？ 6）生物体的适应性景观如何取决于构成蛋白质的分子特性（例如稳定性）？这些问题将使用包括分析理论的多工具方法来解决，该方法将使用粗粒子和蛋白质结构的详细显微镜进化模型进行模拟以及蛋白质结构的现实代表和实验研究，涉及新开发的野生型和突变体的竞争性荧光测定，以作为模型系统。公共卫生相关性：这项理论和实验研究旨在发现蛋白质结构和功能如何响应生物的功能需求而发展。它将有助于确定负责自身免疫性和免疫缺陷等疾病的生物学模块，并有助于制定更好的抗病毒策略。