CAREER: Bridging "In Vitro" and "In Vivo" Protein Folding: An Integrated Interdisciplinary Research and Teaching Plan

职业：桥接“体外”和“体内”蛋白质折叠：综合的跨学科研究和教学计划

• 批准号: 0133504
• 负责人: Joan-Emma Shea
• 金额: $ 60.5万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0133504&HistoricalAwards=false
• 关键词: CAREER; Bridging; Vitro; Vivo; Protein

The current understanding of the mechanism by which a protein folds and adopts its biologically active three dimensional structure stems from experimental and theoretical investigations in idealized dilute environments. Under biologically relevant conditions, however, proteins fold in the much more complex cellular environment, where folding is plagued by a number of obstacles. For example, the crowded cytoplasmic environment, sequence mutations and changes in pH or temperature, can all lead to the formation of misfolded or intermediate structures. While recent experimental advances are permitting an exploration of folding in the cell, a theoretical framework and understanding of protein folding in the cellular environment is lacking. This project seeks to bridge the gap in our theoretical knowledge between in vitro and in vivo protein folding. Methods of statistical physics will be used to develop new methods and models to further our understanding of protein folding and to develop a microscopic picture of the kinetics and thermodynamics of protein aggregation. New algorithms based on parallel tempering Molecular Dynamics, Stationary Phase Monte Carlo and Field Theoretic methods will be developed to efficiently sample relevant aggregate conformations. The effect of crowding on folding and the competition between folding, misfolding and aggregation will be addressed. The educational goals of this project relate to the interdisciplinary nature of this research. A reform of the chemistry curriculum, to reflect the growing interdisciplinary nature of biochemical research and the impact of computers in modern research, will be achieved through the development of a new computational biophysics and chemistry course as well as through the creation of an interdisciplinary undergraduate research program. Outreach activities will be pursued through introductory computer classes aimed at middle school girls.

目前对蛋白质折叠和采用其生物活性三维结构的机制的理解源于理想稀释环境下的实验和理论研究。然而，在生物学相关的条件下，蛋白质在更复杂的细胞环境中折叠，折叠受到许多障碍的困扰。例如，拥挤的细胞质环境、序列突变以及pH或温度的变化，都可能导致错误折叠或中间结构的形成。虽然最近的实验进展允许探索细胞中的折叠，但缺乏细胞环境中蛋白质折叠的理论框架和理解。该项目旨在弥合我们在体外和体内蛋白质折叠之间的理论知识差距。统计物理学的方法将用于开发新的方法和模型，以进一步我们对蛋白质折叠的理解，并开发蛋白质聚集动力学和热力学的微观图像。基于平行回火分子动力学、固定相蒙特卡罗和场论方法的新算法将被开发，以有效地采样相关的聚集体构象。讨论了拥挤对折叠的影响以及折叠、错误折叠和聚集之间的竞争。该项目的教育目标与本研究的跨学科性质有关。化学课程的改革将通过开设新的计算生物物理和化学课程以及创建跨学科的本科研究项目来实现，以反映生物化学研究日益增长的跨学科性质和计算机在现代研究中的影响。将通过针对中学女生的计算机入门课程开展推广活动。