Study of Biological Evolution of Structure and Function in Proteins

描述（由申请人提供）：拟议研究的总体目标是在其载体生物达尔文进化的背景下研究蛋白质的结构、生物物理特性和功能的进化。在过去的预算期间，我们通过引入丰富，强大但易于处理的蛋白质进化多尺度模型，通过直观而现实的基因型-表型关系从基因组序列中获得生物体适应性，从而显著地推进了这一目标，该基因型-表型关系将蛋白质的生物物理和功能特性与重要的表型性状（如细胞分裂）联系起来。在这里，我们将进一步发展这种方法，增加更多的现实主义的模型，包括处理蛋白质的序列为基础的多尺度模型在原子分辨率，原型大肠杆菌糖酵解途径，错误折叠的健身效果和蛋白质丰度的影响。将解决的具体问题包括人口生态学对蛋白质的关键生物物理特性的影响，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;从物理现实模型中的基因组学数据重建祖先序列和分子同源性，蛋白质稳定性，细胞质丰度之间的关系，以及它们的进化速度。多尺度模型的预测和见解将通过高通量生物信息学分析和实验进行有力的测试。本文提出的实验研究包括测量具有各种生态参数（例如种群大小和/或突变率）的细菌的几个蛋白质组中具有统计学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，并将其分析放在坚实的进化和生物物理基础上。

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.