Theoretical Studies of Peptide Structures

肽结构的理论研究

• 批准号: 7758232
• 负责人: Joseph J Dannenberg
• 金额: $ 30.1万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758232
• 关键词: Affect; Alzheimer' s Disease; Amino Acid Sequence; Amino Acids; Attention; Biological; Characteristics; Chemicals; Collaborations; Collagen; Development; Diagnostic; Disease; Ehlers-Danlos Syndrome; Environment; Epidermolysis Bullosa Dystrophica; Funding; Gases; Glean; Goals; Grant; Hereditary nephritis; Hydrogen Bonding; Individual; Knowledge; Laboratories; Measurement; Mechanics; Metaphyseal chondrodysplasia; Methods; Mutate; Mutation; Nature; Oligopeptides; Osteogenesis Imperfecta; Paper; Pattern; Peptides; Phase; Physiological; Positioning Attribute; Property; Proteins; Publishing; Relative (related person); Research; Solvents; Structure; Surface; Symptoms; Theoretical Studies; United States National Institutes of Health; Work; base; density; improved; molecular orbital; peptide structure; protein misfolding; quantum; tau Proteins; tau aggregation; theories; triple helix

DESCRIPTION (provided by applicant): Protein misfolding and abnormal aggregation is known to be characteristic of many diseases and often coincident with peptide mutations. Our long-term goal is to understand the effects of peptide mutations upon the relative energies of the various peptide secondary structures and how they are related to these diseases, with particular emphas placed on diseases related to collagen structure and Alzheimer's disease. With respect to the collagen related diseases, we suggest that these mutations cause errors in the H-bonding patterns of normal collagen. With respect to Alzheimer's disease, we suspect that mutations affect the relative amounts and positions of local alpha-helical structure in the protein, tau, which can change its propensity to be phosphoylated. Hyperphosphorylation has been directly related to the abnormal aggregation of tau which is a physiological symptom of Alzheimer's Disease. The specific aims of the proposed work will be the elucidation the structural factors that determine that determine the secondary structures of peptides using density functional and semi empirical molecular orbital theory, both in isolated (gas phase) and solvated completely geometrically optimized oligopeptides. This work will be coordinated with NMR structural determinations of the same peptides where possible. A second aim will be the application of these and other similar energetic studies to the improved understanding of the details of several diseases that involve mutated, misfolded and/or unnaturally aggregated peptides and proteins. The specific foci of these studies will be collagen-like triple helices (related to osteogenesis imperfecta, Ehlers-Danlos syndrome, Alport syndrome, Schmid metaphyseal chondrodysplasia and dystrophic epidermolysis bullosa) and the protein tau (involved in Alzheimer's disease). First principles (quantum mechanical) calculations will be used to determine the relative energies of the secondary structures of different peptides. The knowledge gleaned from these studies will be applied to determining the properties misfolded proteins that cause several diseases.

描述（由申请人提供）：已知蛋白质错误折叠和异常聚集是许多疾病的特征，并且通常与肽突变同时发生。我们的长期目标是了解肽突变对各种肽二级结构相对能量的影响以及它们与这些疾病的关系，特别强调与胶原蛋白结构和阿尔茨海默病相关的疾病。对于与胶原蛋白相关的疾病，我们认为这些突变会导致正常胶原蛋白的氢键模式出现错误。对于阿尔茨海默病，我们怀疑突变会影响蛋白质 tau 中局部 α 螺旋结构的相对数量和位置，从而改变其磷酸化倾向。过度磷酸化与 tau 蛋白异常聚集直接相关，tau 蛋白异常聚集是阿尔茨海默病的生理症状。拟议工作的具体目标是利用密度泛函和半经验分子轨道理论阐明决定肽二级结构的结构因素，无论是在分离的（气相）还是溶剂化的完全几何优化的寡肽中。这项工作将尽可能与相同肽的 NMR 结构测定相协调。第二个目标是应用这些和其他类似的能量研究来更好地了解涉及突变、错误折叠和/或非自然聚集的肽和蛋白质的几种疾病的细节。这些研究的具体重点是胶原蛋白样三螺旋（与成骨不全、埃勒斯-当洛斯综合征、阿尔波特综合征、施密德干骺端软骨发育不良和营养不良性大疱性表皮松解症有关）和 tau 蛋白（与阿尔茨海默病有关）。第一原理（量子力学）计算将用于确定不同肽二级结构的相对能量。从这些研究中收集的知识将应用于确定导致多种疾病的错误折叠蛋白质的特性。