Simulations on the early events of TTR amyloidogenesis

TTR 淀粉样变早期事件的模拟

基本信息

批准号：
6846762
负责人：
Shuanghong Huo
金额：
$ 21.69万
依托单位：
CLARK UNIVERSITY (WORCESTER, MA)
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6846762
关键词：
acid base balance amyloid proteins amyloidosis binding sites computational biology conformation pathologic process protein binding protein folding protein protein interaction protein structure thyroid hormone binding protein

项目摘要

Our long-term goal is to understand, in detail, the mechanism of amyloid formation from various non-homologous amyioidogenic proteins, to elucidate the relationship between protein misfolding and amyloid diseases, and to develop therapeutic models for inhibition of amyloid formation. In this proposal, we focus on the study of early events along the pathway of human transthyretin (TTR) amyloid formation using computational approaches at the atomic level. We propose three specific aims: Aim 1: A computational study of the energy landscapes, conformational transition pathways, and concerted motions. It is highly likely that the stability and flexibility of monomedc TTR play crucial roles in the early steps of amyloid formation, thereby, it is essential to characterize the initial conformational changes of monomeric I-FR. We begin with simulations of the wild-type TTR monomer and its mutants to characterize their dynamic properties, map the energy landscapes, and search for likely conformational transition pathways connecting the native state and the intermediate states of TTR. By comparing the wild-type with the amyloidogenic mutants, we will provide insights on the differential amyloidogenesis. Aim 2: To study the pH dependence of structure, pH is a crucial factor of the condition which facilitates conformational changes. How does the solution pH influence the tetramedc and monomeric structure of TTR? We propose to perform simulations at constant pH. We will employ a novel algorithm to generate ensembles of protonation states satisfying Boltzmann distribution. By analyzing the population of each protonation state and the generated trajectories, we will provide information on the structural changes as a function of pH. Aim 3: To identify the most favorable binding mode of small molecules bound to TTR and design Imodifications of the ligand that optimize its most favorable binding mode. We propose to study the role of protein-small molecule interaction in stabilizing the tetrameric native state of TTR, to identify the most favorable ligand binding mode among the multiple binding modes with a novel free energy calculation method, and to optimize the ligands to enhance binding affinity. The proposed calculations will provide insight into the small-molecule strategy for intervening in the pathology of TTR related amyioid diseases.

我们的长期目标是详细了解各种非同源淀粉样蛋白形成淀粉样蛋白的机制，阐明蛋白质错误折叠与淀粉样蛋白疾病之间的关系，并开发抑制淀粉样蛋白形成的治疗模型。在本提案中，我们重点研究使用原子水平的计算方法沿着人转甲状腺素蛋白（TTR）淀粉样蛋白形成途径的早期事件。我们提出了三个具体目标：目标 1：能量景观、构象转变路径和协同运动的计算研究。 monomedc TTR 的稳定性和灵活性很可能在淀粉样蛋白形成的早期步骤中发挥至关重要的作用，因此，有必要表征单体 I-FR 的初始构象变化。我们首先模拟野生型 TTR 单体及其突变体，以表征其动态特性，绘制能量图，并寻找连接 TTR 天然状态和中间状态的可能构象转变途径。通过比较野生型与淀粉样蛋白生成突变体，我们将提供关于淀粉样蛋白生成差异的见解。目标 2：为了研究结构的 pH 依赖性，pH 是促进构象变化的条件的关键因素。溶液 pH 值如何影响 tetramedc 和 TTR 的单体结构？我们建议在恒定 pH 值下进行模拟。我们将采用一种新颖的算法来生成满足玻尔兹曼分布的质子化状态的集合。通过分析每个质子化态的总体和生成的轨迹，我们将提供有关作为 pH 函数的结构变化的信息。目标 3：确定小分子与 TTR 结合的最有利的结合模式，并设计配体的修饰以优化其最有利的结合模式。我们建议研究蛋白质-小分子相互作用在稳定TTR四聚体天然状态中的作用，通过新颖的自由能计算方法确定多种结合模式中最有利的配体结合模式，并优化配体以增强结合亲和力。所提出的计算将为干预 TTR 相关淀粉样疾病的病理学小分子策略提供见解。