Modeling Crowding and Confinement of Cellular Environments

描述（由申请人提供）：细胞内拥挤和分隔的环境与体外和生物大分子的硅生物物理研究中典型的稀释条件非常不同。该项目的长期目标是解决大分子拥挤和限制如何以及在多大程度上影响生物分子的热力学和动力学特性的基本问题，并定量重建体内环境对这些特性的影响。该项目有三个组成部分。目标1是为拥挤发展现实的理论模型，提供物理洞察力，但允许结合分子细节。目的2是对蛋白质与原子细节分子的相互作用进行模拟和计算，从而与体外实验进行直接的定量比较。目的3是通过体外实验验证理论预测。测试问题包括拥挤对蛋白质折叠和蛋白质结合的热力学和动力学的影响。该项目将克服当前方法的一些主要限制，并在定量重建体内环境影响方面取得重大进展。

DESCRIPTION (provided by applicant): The crowded and compartmentized environments inside cells are very different from the typical dilute conditions of in vitro and in silico biophysical studies of biomacromolecules. The long-term objectives of this project are to address the fundamental questions of how and how much macromolecular crowding and confinement affect thermodynamic and kinetic properties of biomolecules and to quantitatively reconstruct the influences of in vivo environments on these properties. The project has three integral components. Aim 1 is to develop realistic theoretical models for crowding, which provide physical insight and yet allow for incorporation of molecular details. Aim 2 is to carry out simulations and calculations for the interactions of proteins with atomistically detailed crowders, thereby direct quantitative comparison with in vitro experiments can be made. Aim 3 is to validate theoretical predictions by in vitro experiments. Test problems encompass effects of crowding on the thermodynamics and kinetics of protein folding and protein binding. This project will overcome some of the major limitations of current approaches and make significant advances toward quantitatively reconstructing the influences of in vivo environments. PUBLIC HEALTH RELEVANCE: The proposed research will lead to a deeper understanding of biological processes inside cells and of pathological conditions such as Parkinson's disease in particular. This understanding may form the foundation for more accurate prognoses of and better therapies against such diseases.