研究期間：10108~10207;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.
