Atomistic Studies of Nucleation and Oligomerization in Polyglutamine Aggregation

描述(申请人提供)：我们的目标是对聚谷氨酰胺聚集中的成核和寡聚的机制有一个准确的了解。我们的研究将基于分子模拟和荧光相关光谱(PCS)实验的结合。聚谷氨酰胺聚集是一种核依赖过程，与包括亨廷顿病在内的九种不同神经系统疾病的发生和发展直接相关。成核机制的细节与体内聚集相关，因为毒性被归因于早期中间体填充在形成大聚集的路径上或离开形成大聚集的路径。为了判断聚谷氨酰胺聚集成核的不同方案，我们需要对含有聚谷氨酰胺的体系中的链齐聚进行详细的模拟。为此，我们开发了一个高效而准确的模拟引擎，它允许我们模拟不同长度的多个聚谷氨酰胺分子的构象和相平衡。该引擎名为Absinth，用于使用隐式新型可调哈密顿量研究生物分子的聚集，该引擎基于一种新的方法来模拟多肽与水的平均场相互作用以及多肽内部和之间的水中介相互作用。我们现在可以通过寻求以下问题的答案来测试聚谷氨酰胺分子的成核和齐聚的特定假设：1.增加聚谷氨酰胺长度是否稳定了分子内的3-片状结构或降低了形成这些结构的障碍？2.不稳定的、部分膨胀的构象是否具有关键数量的(3-片状接触)比亚稳定的、致密的(3-片状)更适合聚谷氨酰胺齐聚成核？3.总体溶剂质量和序列背景的扰动如何影响聚谷氨酰胺的构象波动，这些波动如何改变聚谷氨酰胺的相行为？

DESCRIPTION (provided by applicant): Our goal is to obtain an accurate understanding of the mechanism of nucleation and oligomerization in polyglutamine aggregation. Our studies will be based on a combination of molecular simulations and fluorescence correlation spectroscopy (PCS) experiments. Polyglutamine aggregation, a nucleation- dependent process, is of direct relevance to the onset and progression of nine different neurological diseases, including Huntington's disease. Details of nucleation mechanisms are relevant for in vivo aggregation given the toxic given the toxic roles ascribed to early intermediates populated on or off the pathways to formation of large aggregates. To adjudicate between the different proposals for nucleation of polyglutamine aggregation, we need detailed simulations of chain oligomerization in systems containing polyglutamine. Toward this end, we developed an efficient and accurate simulation engine, which allows us to simulate conformational and phase equilibria for multiple polyglutamine molecules of varying lengths. This engine named ABSINTH, for Aggregation of Biomolecules Studied using Implicit Novel Tunable Hamiltonians is based on a new method for modeling mean-field interactions of polypeptides with water and water-mediated interactions within and between polypeptides. We can now test specific hypotheses for nucleation and oligomerization of polyglutamine molecules by seeking answers to questions listed below: 1. Does increasing polyglutamine length stabilize intramolecular 3-sheets or reduce the barrier to the formation of these structures? 2. Are unstable, partially swollen conformations characterized by a critical number of (3-sheet contacts better suited than metastable, compact, (3-sheets for nucleation of polyglutamine oligomerization? 3. How do perturbations in overall solvent quality and sequence context influence conformational fluctuations of polyglutamine and how do these fluctuations alter the phase behavior of polyglutamine?