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执行所需功能的系统了解，我们注释和识别可能是治疗疾病的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，但在缺乏将蛋白质的分子特性与携带基因组的生物体的功能约束和进化要求联系起来的理论的情况下，不可能进行系统的分析。这一提议旨在发展这样的理论，即在携带蛋白质的生物体的达尔文进化的背景下研究蛋白质的分子进化。本文提出的理论和实验研究旨在解决以下问题：1)在生物体的环境和竞争约束下，蛋白质结构的现代宇宙是如何在早期生物进化中进化的？为什么一些蛋白质折叠在许多蛋白质中被过度表达，而有些是独一无二的？2)生物如何适应极端的环境条件，这种适应是如何在其基因组和蛋白质组的组成和结构中表现出来的？3)新的蛋白质功能，如纠错，在从RNA到DNA世界的转换过程中是如何演变的？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，它是如何反映在他们的系统发育谱中的？5)蛋白质-蛋白质相互作用如何导致免疫反应的进化？6)生物体的适应格局如何取决于组成它的蛋白质的分子属性(如稳定性)？这些问题将使用多工具方法来解决，其中包括分析理论，使用粗粒度和逼真的蛋白质结构表示来模拟详细的微观进化模型，以及将新开发的野生型和突变型大肠杆菌的竞争荧光分析作为模型系统的实验研究。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是如何随着生物体的功能需求而演变的。它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，并将有助于制定更好的抗病毒战略。

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.