Modeling Crowding and Confinement of Cellular Environments

描述(申请人提供)：细胞内拥挤和分隔的环境与生物大分子的体外和硅生物物理研究中的典型稀释条件有很大的不同。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性质的基本问题，并定量重建体内环境对这些性质的影响。该项目由三个组成部分组成。目标1是开发现实的拥挤理论模型，这些模型提供物理洞察力，同时允许结合分子细节。目标2是模拟和计算蛋白质与原子细节分子的相互作用，从而与体外实验进行直接的定量比较。目标3是通过体外实验来验证理论预测。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局限性，并在定量重建体内环境的影响方面取得重大进展。 公共卫生相关性：拟议的研究将导致对细胞内生物过程的更深入了解，特别是对帕金森氏症等病理情况的了解。这一认识可能会为更准确地预测此类疾病和更好地治疗此类疾病奠定基础。

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.