A molecular dynamics study of Amyloid Beta peptide structure near lipid bilayers

脂质双层附近β淀粉样蛋白肽结构的分子动力学研究

• 批准号: 7674379
• 负责人: Charles Davis
• 金额: $ 2.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674379
• 关键词: Adopted; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Binding; Cell membrane; Cell physiology; Cereals; Cessation of life; Characteristics; Charge; Cholesterol; Coupled; Disease; Electrostatics; Environment; Fluorescence; Free Energy; Future; Goals; Incidence; Lead; Life Expectancy; Light; Lipid Bilayers; Lipids; Mediator of activation protein; Membrane; Membrane Microdomains; Methods; Modeling; Modern Medicine; Morphology; Muscle Rigidity; Neurodegenerative Disorders; Neurons; Nuclear Magnetic Resonance; Parkinson Disease; Pathology; Peptides; Pharmaceutical Preparations; Process; Research; Role; Sampling; Scheme; Solutions; Staging; Structure; Surface; System; Techniques; Testing; Vesicle; Work; abeta accumulation; aged; aggregation pathway; beta pleated sheet; insight; membrane model; molecular dynamics; monomer; neurotoxicity; peptide structure; preference; prevent; prospective; protein aggregate; protein aggregation; protein misfolding; relating to nervous system; research study; simulation

DESCRIPTION (provided by applicant): Neurodegenerative disorders are a major cause of sickness and death throughout the world. Many of these disorders represent a class of protein aggregation diseases wherein small misfolded proteins aggregate and lead to deteriorating cellular function. To determine appropriate treatments and potential cures for these disorders, it is imperative to understand the mechanism by which proteins misfold and aggregate. The long- term research goal of this work is to identify factors in aged neurons that promote formation of toxic structures common to aggregation disorders, in particular Alzheimer's disease. In Alzheimer's disease, the Amyloid Beta (A Beta) peptide is the probable aggregate species. In experiments, A Beta does not aggregate at low peptide concentrations, but the addition of lipids as vesicles or bilayers to a low concentration of A Beta peptides leads to aggregation. To better understand the mechanism by which lipids influence A Beta aggregation, the objective of this proposal is to determine if lipid bilayers stimulate aggregation by directly promoting a conversion to a fibril-like morphology in peptides. We hypothesize that conversion of A Beta peptides to Beta-sheet structure characteristic of fibrils is (1) directly influenced by electrostatic interactions with the surface of anionic lipid bilayers and (2) promoted by interactions with the surface of rigid, cholesterol-rich lipid rafts. We also hypothesize that bilayers of high cholesterol content promote fibril formation by preventing A Beta insertion into the bilayer, which sequesters A Beta from the pool of soluble peptides available for aggregation. In specific aim 1, molecular dynamics (MD) simulations will be used to determine if the charge of lipid headgroups influence A Beta structure and binding free energies near the membrane surface. In specific aim 2, MD simulations will ascertain, by free energy and secondary structure calculations, if bilayer rigidity affects interactions between A Beta and the surface of binary lipid/cholesterol mixtures of varying cholesterol content. In specific aim 3, both the free energy of insertion of A Beta into bilayers and the free energy of two peptides associating within bilayers of varying cholesterol content will be calculated from MD simulations, which will provide insight into potential pore formation by A Beta. The results of this work will provide details on a single peptide level to determine the role of membranes in the A Beta aggregation pathway. Using these results, coupled with experimental work on A Beta aggregation, a clearer description of A Beta aggregation and its function in neuron toxicity in Alzheimer's disease can be used to develop treatments to either halt the progression or possibly prevent and cure one of the most lethal neurodegenerative disorders, Alzheimer's disease.

描述（由申请人提供）：神经退行性疾病是全球疾病和死亡的主要原因。许多这些疾病代表了一类蛋白质聚集性疾病，其中小的错误折叠蛋白质聚集并导致细胞功能恶化。为了确定这些疾病的适当治疗和潜在治愈方法，必须了解蛋白质错误折叠和聚集的机制。这项工作的长期研究目标是确定老化神经元中促进聚集性疾病（特别是阿尔茨海默病）常见毒性结构形成的因素。在阿尔茨海默病中，β淀粉样蛋白（A β）肽是可能的聚集体。在实验中，A - β在低肽浓度下不会聚集，但在低浓度的A - β肽中添加脂质作为囊泡或双层导致聚集。为了更好地理解脂质影响A β聚集的机制，本提案的目的是确定脂质双分子层是否通过直接促进多肽向原纤维样形态的转化来刺激聚集。我们假设A β肽向原纤维β片结构特征的转化：(1)受到与阴离子脂质双层表面的静电相互作用的直接影响，(2)受到与刚性、富含胆固醇的脂质筏表面的相互作用的促进。我们还假设，高胆固醇含量的双分子层通过阻止A β插入双分子层来促进纤维的形成，双分子层将A β从可用于聚集的可溶性肽池中隔离出来。在具体目标1中，分子动力学（MD）模拟将用于确定脂质头基团的电荷是否影响膜表面附近的A β结构和结合自由能。在特定目标2中，MD模拟将通过自由能和二级结构计算来确定双层刚性是否会影响A β与不同胆固醇含量的二元脂/胆固醇混合物表面之间的相互作用。在具体目标3中，将通过MD模拟计算A β插入双分子层的自由能和在不同胆固醇含量的双分子层内结合的两种肽的自由能，这将为A β潜在的孔隙形成提供见解。这项工作的结果将提供单个肽水平的细节，以确定膜在a β聚集途径中的作用。利用这些结果，再加上对A - β聚集的实验工作，对A - β聚集及其在阿尔茨海默病神经元毒性中的功能的更清晰的描述，可以用于开发治疗方法，以阻止疾病的进展，或者可能预防和治愈最致命的神经退行性疾病之一——阿尔茨海默病。