Thermodynamics and Kinetics of Protein Aggregation

该项目的目的是研究蛋白质折叠/展开的问题，特别是伴侣蛋白DnaK对这一过程的调解。这个项目包括模型研究和实验研究。首先，研究折叠聚集竞争。测量不同外部条件下的蛋白间相互作用，例如温度、pH值和离子强度，将有助于确定对整体蛋白间电位的单独贡献及其在分子结合中的作用。首席研究员（pi）开发了一个三维周期性蒙特卡罗模拟器，用于捕获最初未展开的蛋白质样链的再折叠和聚集之间的竞争。在这个系统中，将考虑短长度尺度上的各种相互作用。此外，pi预测，预折叠蛋白的存在提高了未折叠蛋白的折叠率，因为表面相互作用增强。这为模拟在体内至关重要的伴侣-未折叠蛋白相互作用提供了基础。其他计算任务包括理解再折叠过程的动力学，因为折叠和未展开的形式在热力学上都是可行的，因此动力学可以定义折叠的总体程度。

The objective of this project is to investigate the problem of protein folding/unfolding, and in particular, the mediation of this process by the chaperone DnaK. This project involves both modeling and experimental studies. First, folding-aggregation competition will be studied. Measurements of interprotein interactions at varied external conditions, e.g. temperature, pH, and ionic strength, will help identify separate contributions to the overall interprotein potentials and their role in molecular association. The Principal Investigators (PIs) have developed a three dimensional periodic Monte Carlo simulator for capturing the competition between refolding and aggregation of initially unfolded protein-like chains. In this system various interactions on short length scales will be considered. Also, the PIs have predicted that the presence of pre-folded proteins improves the folding rate of unfolded proteins because of enhanced surface interactions. This provides a basis for modeling the chaperone-unfolded protein interaction so crucial in vivo. Other computational tasks include an understanding of the kinetics of the refolding process, since both folded and unfolded forms are thermodynamically feasible so that the kinetics may define the overall extent of folding.