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Thermodynamics and structural description of Amyloid-beta 1-42 and pyroglutamate-modified Amyloid-beta 3-42 peptides binding to fibrils.

淀粉样蛋白-β 1-42 和焦谷氨酸修饰的淀粉样蛋白-β 3-42 肽与原纤维结合的热力学和结构描述。

基本信息

批准号：
394775642
负责人：
Dr. Bogdan Barz
金额：
--
依托单位：
Institut für Physikalische Biologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/394775642?language=en
关键词：
Thermodynamics structural description Amyloid beta

项目摘要

Alzheimer disease (AD) is the most common type of dementia and it manifests through the deterioration of cognitive domains related to memory. One of the proteins involved in AD is the amyloid beta (AB) protein whose aggregating behaviour and small oligomers are highly associated with neuronal death. The production of toxic oligomers has been recently shown to be greatly enhanced if fibrils are present in the environment. This type of biochemical reaction catalyzed by the fibril surface, known as secondary nucleation, leads to an exponential production of oligomers. However, little information is known about the details of the basic molecular interactions between AB monomers and the fibril surface, including the energetics of monomer binding to the fibril or the conformations adopted by these monomers. Besides AB42, pyroglutamate AB3-42 (pEAB3-42) is one of the main constituents of amyloid plaques, more toxic than AB42, and was hypothesized to strongly attach to AB42 fibrils. In this project we aim at elucidating at atomistic detail the interactions between AB monomers and AB fibrils by combining enhanced all-atom molecular dynamics simulations with surface plasmon resonance experiments. We will focus on AB42 and pEAB3-42, the most toxic alloforms of AB found in amyloid plaques. Our main goal is to calculate the binding affinity and enthalpy of AB42 and pEAB3-42 monomers for AB42 fibrils from simulations and experiments and to resolve the structural conformation of the peptide during binding. Computationally, this will be achieved by calculating the binding affinity of monomers for fibrils using the umbrella sampling method for calculating potentials of mean force in combination with Hamiltonian replica exchange simulations. We will target the fibril edges and the fibril sides and consider a recently derived AB42 fibril model that includes all amino acids. To calculate the binding enthalpy we will study the temperature dependence of the binding process from Arrhenius plots and vant Hoff analysis. Experimentally, the binding affinity will be calculated from fibril washing experiments and SPR measurements. The detachment of peptides from the fibril surface is expected to exhibit a combination of linear and exponential behaviours, specific to detachment from the fibril end and from the fibril surface, respectively. The amplitude of the exponential function for different monomer concentrations will lead to Langmuir adsorption isotherms, and thus the critical monomer concentration associated with the binding affinity for the fibril surface. Thus we will describe thoroughly for the first time, using both computational and experimental methods, the energetics and structure of AB42 and pEAB3-42 peptides binding to the fibrils.

阿尔茨海默病（AD）是最常见的痴呆症，其表现为与记忆相关的认知领域的恶化。 AD 中涉及的蛋白质之一是淀粉样蛋白 (AB)，其聚集行为和小寡聚体与神经元死亡高度相关。最近研究表明，如果环境中存在原纤维，有毒低聚物的产生会大大增加。这种由原纤维表面催化的生化反应（称为二次成核）会导致低聚物呈指数增长。然而，关于 AB 单体和原纤维表面之间基本分子相互作用的细节知之甚少，包括单体与原纤维结合的能量或这些单体所采用的构象。除了 AB42 之外，焦谷氨酸 AB3-42 (pEAB3-42) 是淀粉样蛋白斑的主要成分之一，比 AB42 毒性更大，并且被假设与 AB42 原纤维牢固附着。在这个项目中，我们的目标是通过将增强的全原子分子动力学模拟与表面等离子体共振实验相结合，从原子细节上阐明AB单体和AB原纤维之间的相互作用。我们将重点关注 AB42 和 pEAB3-42，它们是淀粉样蛋白斑中发现的毒性最强的 AB 同种异型。我们的主要目标是通过模拟和实验计算 AB42 和 pEAB3-42 单体对 AB42 原纤维的结合亲和力和焓，并解析结合过程中肽的结构构象。在计算上，这将通过使用伞式采样方法计算单体对原纤维的结合亲和力来实现，该方法用于计算平均力的势并结合哈密顿复制品交换模拟。我们将针对原纤维边缘和原纤维侧面，并考虑最近衍生的包含所有氨基酸的 AB42 原纤维模型。为了计算结合焓，我们将通过阿伦尼乌斯图和范特霍夫分析研究结合过程的温度依赖性。实验上，结合亲和力将通过原纤维洗涤实验和 SPR 测量来计算。肽从原纤维表面的脱离预计会表现出线性和指数行为的组合，分别特定于从原纤维末端和原纤维表面的脱离。不同单体浓度的指数函数的幅度将导致朗缪尔吸附等温线，因此临界单体浓度与原纤维表面的结合亲和力相关。因此，我们将首次使用计算和实验方法彻底描述 AB42 和 pEAB3-42 肽与原纤维结合的能量学和结构。