Effects of macromolecular crowding on protein structure, folding, and interactions

蛋白质折叠是一个重要的生物学过程，因为蛋白质需要折叠成独特的结构才能在细胞中发挥适当的功能。由于细胞内复杂相互作用的干扰，活体标本的实验很难进行。这个项目的目的是利用实验和计算相结合的方法来研究拥挤剂存在下蛋白质折叠的统计和动力学特性。对这种复杂系统的研究涵盖了几个数量级的空间和时间尺度，需要粗粒度分子模拟和细粒度原子模拟的技术。这些方法将战略性地整合到一个多尺度的方法中，使研究现实条件下的蛋白质动力学成为可能。从这项研究中获得的知识将用于发现体内蛋白质折叠的物理原理，并预测只能在细胞内部看到的新现象。集成的多尺度建模和仿真方法将应用于提高生命系统中复杂蛋白质动力学的知识。该项目将促进与瑞典Pernilla Wittung-Stafshede博士研究组的国际研究合作。该项目将包括通过在休斯敦大学进行物理、化学和生物学跨学科领域的实践研究来培训本科生和研究生。休斯敦大学是美国种族最多样化的研究型大学之一。学生将学习高性能计算的范例，分子模拟的算法，以及在分子水平上更好地理解生物系统的物理原理。新开发的多尺度建模和仿真软件将通过互联网提供给科学界。PI计划在她定期访问休斯顿地区的高中时使用该软件，并继续鼓励妇女和代表性不足的群体从事科学和工程方面的职业。PI还计划为本科生和高中教师举办夏季教育研讨会，让参与者获得将该软件应用于生物物理学研究的实践经验，作为影响科学教育的有效教学方法。

Protein folding is an important biological process because proteins are required to fold into unique structures for proper functionality in cells. Experiments on living specimens are difficult to perform because of the interference from complex interactions in a cell. The aim of this project is to investigate statistical and kinetic properties of protein folding in the presence of crowding agents using a combined experimental and computational approach. Studies of such complex systems covering several orders of magnitude in spatial and temporal scales require techniques from coarse-grained molecular simulation and fine-grained atomistic simulations. These methods will be strategically integrated into a multi-scale approach which enables the investigation of protein dynamics in realistic conditions. The knowledge obtained from the research will be used to discover physical principles of protein folding in vivo and predict new phenomena that can only be seen in the interior of a cell. An integrated multi-scale modeling and simulation approach will be applied to enhance knowledge of complex protein dynamics in living systems. The project will advance international research collaboration with the experimental group of Dr. Pernilla Wittung-Stafshede in Sweden.This project will involve training of undergraduate and graduate students through hands-on research in the interdisciplinary fields of physics, chemistry and biology at the University of Houston, one of the most ethnically diverse research universities in the country. Students will learn about paradigms for high-performance computing, algorithms for molecular simulations, and physical principles to better understand biological systems at a molecular level. Newly developed multiscale modeling and simulation software will be made available to the scientific community through the internet. The PI plans to include the use of this software in her regular visits to high schools in the Houston area and to continue encouragement of women and underrepresented groups to pursue careers in sciences and engineering. The PI also plans to host summer educational workshops for undergraduate students and high school teachers that will provide participants with hands-on experience in applying this software to biophysics research as an effective teaching and learning approach to impact science education.