MODELING STRUCTURE AND STABILITY OF TAU PROTEIN AGGREGATES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 蛋白质聚集是生物学和工业中的一个基本挑战，因为它在几种神经退行性疾病中起作用，例如阿尔茨海默病、帕金森病、亨廷顿病等。据信，蛋白质聚集体直接参与疾病的病因学。因此，从生物化学和治疗学的角度来看，了解蛋白质聚集体的结构和稳定性是至关重要的。由于它们的大尺寸和低溶解度，用于高分辨率结构测定的现有方法不能成功地产生精确的模型。然而，自旋标记和荧光等技术为我们提供了关于这些聚集体的各种候选结构的重要间接信息。在这里，我们提出了一个基于分子动力学的模拟技术，以获得进一步的了解从实验中获得的候选结构。我们将从实验表明的这些可能的聚集体拓扑结构开始，并进行长时间的分子动力学模拟来研究这些结构的相对稳定性。这通常将针对tau蛋白聚集体进行，以确定其在阿尔茨海默病中的相关性。我们将使用琥珀力场进行这项从头算研究，这将需要高性能的计算。因此，我们相信我们的模拟方法将补充实验室中获得的实验结果，并将为我们提供更好的想法，蛋白质聚集体的稳定性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Protein aggregation is a fundamental challenge in biology and industry for its role in several neurodegenerative diseases such as Alzheimers, Parkinson, Huntington to name a few. It is believed that protein aggregates are directly involved in the etiology of disease. Understanding the structure and stability of protein aggregates is thus of utmost importance from both biochemistry and therapeutics point of view. Because of their large size and low solubility existing methods for high-resolution structure determination have not been successful producing accurate models. However, techniques such as spin labeling and fluoresence give us important indirect information about various candidate structures of these aggregates. Here we propose a molecular dynamics based simulation technique to gain further insight about such candidate structures obtained from experiments. We will start with some of these possible aggregate topologies indicated by experiments and perform long molecular dynamics simulation to study the relative stability of these structures. This will be performed in general for tau protein aggregates for its relevance in Alzheimers disease. We will use Amber force field to carry out this ab initio study which will require high performance computing. Thus we believe our simulation approach will be complementary to experimental results obtained in lab and will provide us with better idea about the stability of protein aggregates.