CAREER: How Do Thermophilic Proteins Withstand High Temperature?

摘要：科学价值：主要从在非常高的温度下生长的生物体中提取的嗜热蛋白，在比中温生物体中的中温蛋白高得多的温度下变性。蛋白质科学中一个长期存在的问题是：选择性压力，如环境温度，如何影响蛋白质耐热性的进化？随着蛋白质组学和系统水平研究的出现，这个问题变得更加值得注意：在高温下生长的细胞如何适应它们的整个蛋白质集合？虽然现有的研究是针对单个蛋白质组的，但一些表征不同蛋白质组的实验数据需要新的理论建模和更大范围的详细分析，以揭示不同生物可能用来抵御这种温度极端的广泛的适应策略。对众多蛋白质进行如此大规模的详细建模将与实验观察相结合，作为该项目的一部分。这项新颖的多尺度研究将能够计算出几个重要的、难以测量的、但已分析的生物物理量，这些物理量对蛋白质的功能和稳定性至关重要，最终决定了生物学。因此，全球范围内微观结构特征与蛋白质热力学的关系将为蛋白质进化和工程提供基本线索。广泛影响：该项目将影响多项外展努力和新的教育倡议。将把与这项工作直接相关的蛋白质科学概念纳入这些外展活动，将其纳入课堂材料、讲习班和示范，以提高公众的认识。将为丹佛大学新推出的分子和细胞生物物理学博士项目设计研究生课程和课程，其中将展示生物学中的定量建模，包括蛋白质折叠、稳定性和进化的概念。这项研究以拼图、动画和海报的形式衍生出的简单概念将在埃利奇花园游乐园举行的科学意识之夜上展示，高中学生和老师都会参加。这个游乐园在不同种族和收入水平之间具有广泛的吸引力，并接触到了更传统的外展方式所不能提供的服务的受众。这些概念还将纳入为当地学校的中学教育工作者举办的短期培训讲习班。丹佛大学的本科生将为他们的高级论文完成部分提案，为此他们将接受科学写作和演讲技能的进一步培训。研究结果和为解释实验数据而开发的代码将在网上免费提供给全球蛋白质科学界。除了对蛋白质科学的直接影响外，这项研究还将影响与蛋白质药物相关的新酶的设计，以及可再生能源载体的生物合成。

Abstract:Scientific Merit: Thermophilic proteins, primarily extracted from organisms that thrive at very high temperatures, denature at significantly higher temperatures than mesophilic proteins from organisms that live at moderate temperatures. One of the long-standing questions in protein science has been: How do selective pressures, such as environmental temperature, impinge on the evolution of thermal tolerance in proteins? With the advent of proteomic and systems level studies that encompass the complete set of proteins in an organism, the question becomes yet more remarkable: How do cells grown at high temperatures adapt their entire collection of proteins? While existing studies are on individual sets of proteins, several experimental data characterizing different proteomes demand new theoretical modeling and detailed analysis at a much larger scale to unravel broad scale adaptive strategies that different organisms may have utilized to withstand such temperature extremities. Such large scale detailed modeling of numerous proteins will be combined with experimental observations as part of this project. The novel multi-scale research will enable computation of several important, hard to measure, yet analyzed biophysical quantities that are central to protein function and stability, ultimately dictating biology. Thus the relationship of microscopic structural features to protein thermodynamics on a global scale will provide essential clues to protein evolution and engineering.Broader Impact: The project will impact multiple outreach efforts and new initiatives for education. Concepts of protein science, directly related to this work will be integrated in these outreach activities by incorporating in class material, workshop, engaging demonstrations for general public awareness. Graduate curricula and courses will be designed for the newly launched Molecular and Cellular Biophysics doctoral program at the University of Denver in which quantitative modeling in biology including concepts of protein folding, stability and evolution, will be showcased. Simple concepts derived from this research in the form of puzzles, animations and posters will be demonstrated at the science awareness night at the Elitch Garden amusement park, attended by high school students and teachers. This amusement park has a broad appeal across ethnic groups and income levels, and reaches audiences underserved by more traditional outreach methods. These concepts will also be integrated in a short-term training workshop for secondary educators from local schools. Undergraduate students at the University of Denver will carry out parts of the proposal for their senior theses, for which they will be further trained in scientific writing and presentation skills. Results of the research, and codes developed to interpret experimental data will be made freely available online to the global protein science community. Besides immediate impact on protein science, the research will also impact design of new enzymes relevant in protein pharmaceuticals as well as biosynthesis of renewable energy carriers.