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

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化稀释环境中的实验和理论研究。然而，在生物学相关条件下，蛋白质在复杂得多的细胞环境中折叠，其中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在细胞中折叠的探索，但缺乏理论框架和对细胞环境中蛋白质折叠的理解。这个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的差距。统计物理学的方法将用于开发新的方法和模型，以进一步了解蛋白质折叠，并开发蛋白质聚集的动力学和热力学的微观图像。新的算法的基础上并行回火分子动力学，固定相蒙特卡罗和场论方法将开发有效地采样相关的聚集体构象。 拥挤的折叠和折叠，错误折叠和聚集之间的竞争的影响将得到解决。本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，以反映生物化学研究和计算机在现代研究中的影响日益增长的跨学科性质，将通过开发新的计算生物物理学和化学课程以及通过创建跨学科的本科生研究计划来实现。将通过针对中学女生的计算机入门课程开展外联活动。

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.