Theoretical Studies of Peptide Structures

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，以及它们如何与这些疾病相关，特别是与胶原结构和阿尔茨海默病相关的疾病。对于胶原蛋白相关疾病，我们认为这些突变导致正常胶原蛋白的氢键模式错误。关于阿尔茨海默病，我们怀疑突变影响蛋白质tau中局部α-螺旋结构的相对数量和位置，这可以改变其被磷酸化的倾向。过度磷酸化与tau的异常聚集直接相关，tau的异常聚集是阿尔茨海默病的生理症状。所提出的工作的具体目标将是阐明的结构因素，确定使用密度泛函和半经验分子轨道理论的肽的二级结构，无论是在隔离（气相）和溶剂化完全几何优化的寡肽。在可能的情况下，这项工作将与相同肽的NMR结构测定相协调。第二个目标将是应用这些和其他类似的充满活力的研究，以提高对涉及突变，错误折叠和/或非天然聚集的肽和蛋白质的几种疾病的细节的理解。这些研究的具体焦点将是胶原样三重螺旋（与成骨不全、Ehlers-Danlos综合征、Alport综合征、Schmid干骺端软骨发育不良和营养不良性大疱性表皮病有关）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的二级结构的相对能量。从这些研究中收集到的知识将被应用于确定导致几种疾病的错误折叠蛋白质的特性。

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.