Atomistic Studies of Nucleation and Oligomerization in Polyglutamine Aggregation

描述（由申请人提供）：我们的目标是准确了解聚谷氨酰胺聚集中的成核和寡聚化机制。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。多聚谷氨酰胺聚集是一种成核依赖性过程，与包括亨廷顿病在内的9种不同神经系统疾病的发作和进展直接相关。考虑到毒性作用，成核机制的详细信息与体内聚集相关，毒性作用归因于在形成大聚集体的途径上或途径外聚集的早期中间体。为了在聚谷氨酰胺聚集成核的不同建议之间进行裁决，我们需要详细模拟含有聚谷氨酰胺的系统中的链寡聚化。为此，我们开发了一个高效，准确的模拟引擎，这使我们能够模拟不同长度的多聚谷氨酰胺分子的构象和相平衡。该引擎名为ABSINTH，用于使用隐式新颖可调哈密顿研究生物分子的聚集，是基于一种新的方法，用于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介导的相互作用。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成核和寡聚化的特定假设：1。增加多聚谷氨酰胺的长度是否稳定了分子内的3-折叠或减少了这些结构形成的障碍？2.是不稳定的，部分溶胀的构象特征在于一个临界数的β-片接触更适合于比亚稳，紧凑，β-片的聚谷氨酰胺低聚成核？3.整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，以及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?