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淀粉样蛋白形成的机制，从各种非同源树细胞生成蛋白，以阐明蛋白质错误折叠与淀粉样蛋白疾病之间的关系，并开发治疗模型以抑制淀粉样蛋白的形成。在此提案中，我们专注于对人类经硫代蛋白（TTR）淀粉样蛋白形成途径的早期事件的研究，并使用原子水平的计算方法进行研究。我们提出了三个具体目标：目标1：对能量景观，构象过渡途径和协同动作的计算研究。 MonoMedC TTR在淀粉样蛋白形成的早期步骤中扮演至关重要的角色的稳定性和灵活性很有可能，因此必须表征单体I-FR的初始构象变化。我们从野生型TTR单体及其突变体的模拟开始，以表征其动态特性，绘制能量景观，并寻找可能连接天然状态和TTR中间状态的可能构象过渡途径。通过将野生型与淀粉样生成突变体进行比较，我们将提供有关差异淀粉样生成的见解。目的2：研究结构的pH依赖性，pH是促进构象变化的疾病的关键因素。溶液pH如何影响TTR的Tetramedc和单体结构？我们建议在恒定pH下执行模拟。我们将采用一种新型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状态和生成的轨迹的种群，我们将提供有关pH值的结构变化的信息。 AIM 3：确定与TTR结合的小分子的最有利的结合模式，并设计了优化其最有利结合模式的配体的Imatification。我们建议研究蛋白质 - 小分子相互作用在稳定TTR的四聚体天然状态中的作用，以通过新的自由能计算方法在多个结合模式中识别最有利的配体结合模式，并优化配体以增强结合亲和力。拟议的计算将提供有关介入与TTR相关氨基叶疗法病理学的小分子策略的见解。