CAREER: Understanding Protein Folding Dynamics in the Ultra-Fast Limit

这个项目将在非常快的时间尺度上研究与蛋白质折叠和组装相关的一些独特现象。蛋白质折叠中的纳秒和微秒事件现在可以由实验者使用激光光谱学来探测，也可以由理论家使用最先进的分子动力学模拟来探测。由于许多小的、新设计的蛋白质和多肽快速折叠，超快折叠是蛋白质折叠的实验、理论和设计方面都融合在一起的制度。然而，这也是一种使蛋白质折叠问题的标准物理描述背后的假设和解释变得紧张的制度：快速折叠不同于缓慢折叠。该项目将时间分辨激光光谱学应用于设计的小蛋白质和多肽，以检查折叠的标准跨越障碍描述的局限性，并调查这些描述背后的假设可能如何打破最快折叠分子的假设。它集中在(1)Kramers折叠模型中反应摩擦的含义，(2)展开多肽的快速重组的速度，以及(3)超快折叠预期的与简单跨越动力学的偏差。该项目的更广泛的影响部分来自于它对复杂生化现象的简单物理模型的极限的基本理解的进步，以及它支持时间分辨光谱仪器的事实，该仪器增强了分子生物物理学的科学研究基础设施。该计划的教育部分也产生了更广泛的影响。PI将领导一项针对当地一所中学的K-12外展活动，该中学有大量的少数族裔入学人数和大量的弱势学生。该项目旨在激励和支持更多的这类学生参加可选的科学博览会，在他们开展科学博览会项目的几周内为他们提供定期指导。该计划还为本科生和研究生提供跨学科生物物理的研究性实验室教学和培训：这种培训使物理科学专业的学生开始学习生物系统，并向对生物有兴趣的学生介绍物理仪器和方法。该项目由分子和细胞生物科学部的分子生物物理学计划和数学和物理科学局的物理部共同资助。

This project will investigate some of the unique phenomena associated with protein folding and assembly on very fast time scales. Nanosecond and microsecond events in protein folding can now be probed by experimentalists using laser spectroscopy, and by theorists using state-of-the-art molecular dynamics simulation. Because many small, newly-designed proteins and peptides fold rapidly, ultra-fast folding is the regime where the experimental, theoretical, and design aspects of protein folding all converge. However, it is also a regime that strains the assumptions and interpretations behind standard physical descriptions of the protein folding problem: fast folding is different from slow folding. This project applies time-resolved laser spectroscopy to small, designed proteins and peptides in order to examine the limits of standard barrier-crossing descriptions of folding, and to investigate how the assumptions behind those descriptions may break down for the very fastest folding molecules. It focuses on (1) the meaning of reaction friction in Kramers models for folding, (2) the speed of rapid reorganizations of unfolded polypeptides, and (3) the deviation from simple barrier-crossing kinetics that is expected for ultrafast folding.The broader impact of this project derives in part from its advancement of basic understanding of the limits of simple physical models for complex biochemical phenomena, and from the fact that it supports time-resolved spectroscopic instrumentation that enhances the scientific research infrastructure in molecular biophysics. A broader impact also derives the educational components of the plan. The PI will lead a K-12 outreach effort aimed at a local middle school that has a large minority enrollment and substantial numbers of disadvantaged students. The project aims to motivate and support the participation of more of these students in the optional science fair by providing them with regular mentoring over a period of many weeks as they undertake their science fair projects. The plan also provides for research laboratory teaching and training for undergraduate and graduate students in interdisciplinary biological physics: This training initiates physical-science students into the study of biological systems, and it introduces biologically-inclined students to physical instrumentation and methodologies. This project is jointly funded by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Division of Physics in the Mathematical and Physical Sciences Directorate.