Study of biological evolution of structure and function in proteins

描述（由申请人提供）：由于缺乏对蛋白质和功能模块如何进化以实现所需功能的系统理解，我们注释和识别可能是治疗疾病重要靶点的蛋白质和途径的能力受到限制。虽然基因组计划积累了大量关于蛋白质序列、结构和功能的数据，但如果缺乏将其分子特性与携带基因组的生物体的功能限制和进化要求联系起来的理论，则不可能进行系统分析。这个提议的目的是发展这样的理论，在达尔文进化的背景下研究蛋白质的分子进化携带它们的生物体。本文提出的理论和实验研究旨在解决以下问题：1)在生物的环境和竞争约束下，现代蛋白质结构是如何在早期生物进化中进化的？为什么有些蛋白质折叠在许多蛋白质中被过度代表，而有些则是独特的？2)生物如何适应极端环境条件，这种适应如何在其基因组和蛋白质组的组成和结构中表现出来？3)在从RNA到DNA世界的转化过程中，诸如纠错等新的蛋白质功能是如何进化的？4)生物网络中的参与者——转录因子和上游区域——是如何共同进化的，它是如何反映在它们的系统发育谱上的？5)负责免疫反应的蛋白质-蛋白质相互作用是如何演变的？6)一个有机体的适应性景观是如何依赖于构成它的蛋白质的分子特性（如稳定性）的？这些问题将使用多工具方法来解决，包括分析理论，使用粗粒度和现实的蛋白质结构表示来模拟详细的微观进化模型，以及实验研究，包括新开发的野生型和突变型大肠杆菌的竞争性荧光分析作为模型系统。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根据生物体的功能需求而进化。这将有助于确定导致自身免疫和免疫缺陷等疾病的生物模块，并有助于制定更好的抗病毒策略。

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.