背景: 研究類澱粉蛋白的重要性主要是由於它和大約二十種人類神經退化性疾病有相關性，例如老年癡呆症及帕金森氏症。類澱粉蛋白纖維擁有半規律性的奈米結構，由錯誤折疊的蛋白質自組裝而形成。互異的氨基酸序列均可形成類澱粉蛋白纖維，但卻都共同擁有 “cross-” 的結構特徵。最近研究顯示早期蛋白質聚集生成的oligomers 可能才是真正的細胞毒性物質。由於類澱粉蛋白纖維的複雜性，其生成及毒性的生物物理機制尚未清楚瞭解。研究動機: 研究顯示A的神經毒性與A和細胞膜的交互作用息息相關，因此，從分子觀點了解A和細胞膜交互作用變得極為重要。雖然分子模擬法已被廣泛地使用來研究 A，然而，分子模擬法卻很少用來研究A和細胞膜的交互作用。研究方法及系統:計算方法包括平行淬煉分子動態法搭配implicit 生物膜力場及長時間全原子分子動態模擬法。老年癡呆症的病源-A peptide, 及其家族性突變體是本計劃主要的研究重點。目標: 計劃具體的研究目標主要包括: (1).描繪A在的水-膜介面的折疊，穿膜及聚集的energy landscapes 以了解其生成機制; (2).了解A在的水-膜介面的折疊，穿膜及聚集中的重要交互作用力，提供理論基礎設計藥物以阻止澱粉蛋白的形成; (3).建構A(1-42) 及其家族性突變體纖維在水中或生物膜中的三度空間結構。 Background: The biomedical interests in amyloids are arisen from their association with about 20 human neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Amyloid fibrils are semi-ordered nanostructures as the result of self assembly of proteins when they are misfolded under critical conditions. Amyloid fibrils are formed of diverse polypeptide sequences, but all share similar “cross-” structure. Recent researches suggest that oligomers, forming at the early stage of protein aggregation, may be the actual toxic agents to cells. Due to the complexity of amyloids, the underlying biophysical mechanisms of its formation and toxicity are still unclear. Motivations: Evidences have shown that Aneurotoxicity is related to direct interactions between Apeptide and cell membrane. Thus, it is important to understand Amembrane interaction at the molecular basis in a water-membrane environment. Although Apeptide has been intensively studied using computational simulations, however, less effort was given to study Amembrane interaction computationally. Methodology and Major Studied Systems: Computational Methods include an effective phase space sampling algorithm, replica-exchange molecular dynamics (REMD) associated with implicit membrane model and long time scale all-atom conventional MD simulations, will be employed to answer the motivated questions. A peptide, a causative agent in the etiology of Alzheimer’s disease, and its familial Dutch E22Q-Aβ(1-40), Iowa D23N-Aβ(1-40) and Dutch/Iowa E22Q/D23NAβ( 1-40) double mutants, are the main focus. Objectives: Specific objectives include (1). delineating the interfacial folding, membrane insertion and aggregation energy landscapes of A peptide in a water-membrane environment to understand the mechanism of amyloid formation; (2). characterizing significant interactions governing the interfacial folding, membrane insertion and aggregation of A peptide in a water-membrane environment to provide a theoretical guideline for rational drug design to prevent amyloid formation and its associated diseases.; (3). modeling the 3D protofibril structures of A(1-42)’s familial mutants either in a water or in a water-membrane environment. 研究期間：10008 ~ 10107
