Atomistic Studies of Nucleation and Oligomerization in Polyglutamine Aggregation

聚谷氨酰胺聚集成核和低聚的原子研究

• 批准号: 7800891
• 负责人: ROHIT V PAPPU
• 金额: $ 28.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7800891
• 关键词: Behavior; Cell Nucleus; Characteristics; Complement; Disease; Equilibrium; Fluorescence; Free Energy; Frequencies; Goals; Huntington Disease; Lead; Length; Mediating; Methods; Microscopic; Modeling; Molecular; Molecular Conformation; Names; Nature; Pathway interactions; Peptides; Phase; Process; Reaction; Role; Sampling; Simulate; Solvents; Specific qualifier value; Specificity; Spectrum Analysis; Structure; Swelling; System; Techniques; Testing; Variant; Water; adjudicate; base; design; driving force; in vivo; nervous system disorder; novel; polyglutamine; polypeptide; preference; research study; simulation

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?

描述（由申请人提供）：我们的目标是获得对多谷氨酰胺聚集中成核和寡聚的机制的准确理解。我们的研究将基于分子模拟和荧光相关光谱（PC）实验的组合。聚谷氨酰胺聚集是一种核定依赖性过程，与包括亨廷顿氏病在内的九种不同神经系统疾病的发作和进展直接相关。鉴于毒性作用归因于属于大量大骨料形成的途径或途径的早期中间体的毒性作用，核定机制的细节与体内聚集有关。为了在多谷氨酰胺聚集的各种建议之间进行裁决，我们需要详细的模拟包含多谷氨酰胺的系统中的链寡聚化。为此，我们开发了一种有效，准确的模拟引擎，使我们能够模拟多种长度的多谷氨酰胺分子，模拟构象和相位平衡。这款名为Asbinth的发动机是针对使用隐式新型可调式汉顿量研究的生物分子聚集的，它基于一种新方法，用于建模多肽与多肽内外的水和水介导的相互作用的平均场相互作用。现在，我们可以通过寻找以下列出的问题的答案来检验聚谷氨酰胺分子的成核和寡聚化的特定假设：1。多谷氨酰胺长度是否可以稳定分子内3页或减少对这些结构形成的障碍？ 2。不稳定的，部分肿胀的构象为特征，其特征在于（3个表触点比可稳态，紧凑型更适合（三片用于多谷氨酰胺寡聚成核的核定核）？3。3。扰动如何影响整体质量和序列上下文的整体构象情境影响这些相构象的层压型，这些相平方的多型多核呈现了这些相多的多型多型多型多型多型多型多型多型多型多型多型多核素质波动？