CAREER: Experimental & Computational Studies of Ancient Sm-based RNA Assemblies

智力价值：定义一个有机体的生物信息储存在它的遗传物质(DNA)中，这些遗传物质必须转化为无数的蛋白质，才能组装成一个活的、功能正常的细胞。从DNA到蛋白质涉及许多分子步骤，其中生物分子RNA起着核心作用。事实上，RNA现在被认为是生命之初的祖先分子，因为它既可以存储信息(像DNA)，也可以充当化学催化剂(像蛋白质酶)。一个非凡的、进化上保守的Sm蛋白家族在RNA加工中发挥着关键作用，从人类到古生物分支中的古代单细胞生物。SM介导的途径从真核生物中的mRNA剪接到细菌中由RNA调控的细胞间通讯网络的范围各不相同。在这些途径中，至少有一个关键步骤是由建立在Sm蛋白上的分子组装所介导的。鉴于Sm家族在当代RNA生物学中的普遍存在，古老的Sm蛋白可能在从祖先RNA世界向现代生活的核糖核蛋白(RNP)世界的关键转变中发挥了作用。这个NSF项目关注的是来自深分支古生菌和细菌物种的Sm系统。利用实验(生物化学、蛋白质组学、结晶学)和计算(生物信息学、模拟)，该项目将探索古代基于Sm的RNP复合体的外观(结构)、它们的组装路径和动力学行为(功能)，以及许多Sm系统和它们的RNA伙伴之间的相互关系(进化)。这项工作将有助于发现Sm家族如何演变为构建基于RNA的分子机器的无处不在的支架。该项目的长期目标--破译Sm蛋白在RNA相关分子机器早期进化中的生化作用--也将从分子细节上阐明古代Sm家族在促进从原始RNA世界向现代RNP世界过渡方面的潜在作用。广泛影响：除了其科学影响之外，该项目还将在初级研究方面教育和培训十几名本科生和研究生。由于该项目涉及多个学科，包括生物学(RNA、进化论)、化学(结晶学、分子模拟)和计算机科学(生物信息学)，学生将以一种真正综合和跨学科的方式学习生物科学：驱动问题是生物学，而工具和方法是物理/定量的。同样的多学科方法，将生物学和计算结合起来，是该项目名为UVaCompBio的中心教育计划的基础。UVaCompBio项目的基本模式是生物科学和定量科学(物理、化学、CS等)的本科生。将结对成小组，在一个学期的课程中一起进行积极的学习练习和微型项目，并在计算生物学的几个领域(基于物理和信息学)共同工作。这一努力将(I)使生物科学的学生为数量生物学做好准备，(Ii)让定量科学的本科生在工作中欣赏复杂生物系统的迷人性质。这一双重目标将反过来实现最终目标，即使学生成为无所畏惧的学习者，能够在看似不相关的科学学科之间开展工作。因此，在项目期内，这项教育活动将培训数十名本科生，并将同时直接实现现代科学教育的这两个主要目标，重点是数量生物学和少数群体宣传部分。

Intellectual Merit: The biological information that defines an organism is stored in its genetic material (DNA), which must be converted into myriad proteins to assemble a live, functioning cell. Many molecular steps are involved in going from DNA to protein, with the biomolecule RNA playing a central role. Indeed, RNA is now thought to be the ancestral molecule at the dawn of life, as it can both store information (like DNA) and act as chemical catalyst (like protein enzymes). A remarkable, evolutionarily conserved family of Sm proteins plays key roles in RNA processing, in organisms ranging from humans to ancient single-celled organisms from the Archaeal branch of life. Sm-mediated pathways vary in scope from mRNA splicing in eukaryotes to RNA-regulated inter-cellular communication networks in bacteria. In each of these pathways at least one key step is mediated by a molecular assembly built upon Sm proteins. Given the ubiquity of the Sm family in contemporary RNA biology, ancient Sm proteins may have played a role in the pivotal transition from an ancestral RNA World to the ribonucleoprotein (RNP) world of modern life. This NSF project focuses on Sm systems from deep-branching archaeal and bacterial species. Leveraging both experiment (biochemistry, proteomics, crystallography) and computation (bioinformatics, simulations), the project will explore what ancient Sm-based RNP complexes look like (structure), their assembly pathways and dynamical behavior (function), and the interrelationships amongst the many Sm systems and their RNA partners (evolution). The work will help discover how the Sm family evolved into a pervasive scaffold for the construction of RNA-based molecular machines. The project's long-term objective - to decipher the biochemical roles of Sm proteins in the early evolution of RNA-associated molecular machines - also will illuminate, in molecular detail, the potential roles of the ancient Sm family in facilitating the transition from a primordial RNA world to our modern RNP world.Broader Impacts: Beyond its scientific impact, this project will educate and train over a dozen under-graduate and graduate students in primary research. Because the project overlaps several disciplines, including biology (RNA, evolution), chemistry (crystallography, molecular simulations) and computer science (bioinformatics), students will learn the biological sciences in a truly integrated and interdisciplinary manner: The driving questions are biological, while the tools and approaches are physical/quantitative. This same multidisciplinary approach, uniting biology and computation, is the basis for the project's central educational plan, dubbed UVaCompBio. The basic model of the UVaCompBio project is that undergraduates from the biosciences and the quantitative sciences (physics, chemistry, CS, etc.) will be paired into teams that work together on active learning exercises and mini-projects over the course of an academic term, and in several areas of computational biology (physics- and informatics-based). This effort will (i) prepare students from the biosciences for quantitative biology, and (ii) give undergraduates from the quantitative sciences a working appreciation of the fascinating nature of complex biological systems. That two-fold goal will, in turn, achieve the ultimate goal of empowering students to be fearless learners who can work at the interfaces between seemingly unrelated scientific disciplines. Thus, over the course of the project period this educational initiative will train scores of undergraduate students and, with an emphasis on quantitative biology and a minority outreach component, will simultaneously and directly address these two major goals of modern science education.