Theoretical Studies of Peptide Structures

肽结构的理论研究

• 批准号: 7560203
• 负责人: Joseph J Dannenberg
• 金额: $ 30.4万
• 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/7560203
• 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; 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，通常与肽突变一致。我们的长期目标是了解肽突变对各种肽二级结构的相对能量的影响，以及它们与这些疾病的相关性，特别强调与胶原蛋白结构和阿尔茨海默氏病有关的疾病。关于胶原蛋白相关的疾病，我们建议这些突变在正常胶原蛋白的H键模式下导致错误。关于阿尔茨海默氏病，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，这可能会改变其被磷酸化的倾向。高磷酸化与TAU的异常聚集直接相关，TAU是阿尔茨海默氏病的生理症状。拟议工作的具体目的是阐明使用密度功能和半经验分子轨道理论确定肽的二级结构的结构因子，无论是在分离的（气相）中（气相），并且完全溶剂化了几何优化的寡肽。这项工作将在可能的情况下与同一肽的NMR结构确定协调。第二个目的是将这些和其他类似的能量研究应用于对几种涉及突变，错误折叠和/或不自然聚集的肽和蛋白质的细节的了解。这些研究的具体焦点将是类似胶原蛋白的三重螺旋（与成骨剂，Ehlers-Danlos综合征有关，Alport综合征，Schmid形而上学的软骨增生和营养不良表皮分解Bullosa）和蛋白质Tau（涉及蛋白质tau）第一原理（量子机械）计算将用于确定不同肽的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引起多种疾病的特性错误折叠的蛋白质。