This proposal is a request to continue highly productive research directed at elucidating the fundamental principles underlying amyloid peptide association and aggregation. Aggregation of proteins of known sequence is linked to Alzheimer'sDisease (AD) and other neurodegenerative disorders. Because recent evidence strongly suggests that soluble low molecular weight (LMW) aggregates of amyloidogenic proteins are the primary cause of neurotoxicity, there is urgency in understandingthe molecular mechanisms of LMW oligomer formation. In addition, it is necessary to elucidate the nature of external conditions, including pH, denaturant, and temperature, that can drive conformational fluctuations in the monomeric peptides that make them prone to aggregation. The,long-term goal of the proposed effort is to formulate the fundamental principlesresponsible for polypeptide association and fibril formation. To achieve this goal, a multifaceted approach is proposed that includes the development and use of novel computational methods to probe the early events leading to oligomer formation in A(3-peptides, linked to AD, and human amylin, whose aggregation is implicated in type II diabetes. The effort is comprised of projects directed at four specific aims: (1) All-atom molecular dynamics simulations will be used to probe the effects of sequence variations in the aggregation of A0-peptides. These studies will lead to a map of the assembly pathways in these peptides, as well as provide a molecular-level understandingof the variations in the observed fibrillization rates among naturallyoccurring Ap-peptide mutants. (2) To dissect the factors that contribute to the stability of oligomers of A|3-peptides, the response of interacting Ap-peptides to denaturants, such as urea and guanidinium hydrochloride, will be explored. (3) Computational studies to understand why human amylin aggregates, while amylin from rats does not will be completed. By comparing the results for Ap and amylin peptides, a conceptual framework for understanding sequence and environmentaleffects on association of peptides and proteins will be developed. (4) To discover the general principles of polypeptide association, the detailed moleculardynamics simulations will be supplemented with studies involving coarse-grained off-lattice models of polypeptides. Employingsuch models with realistic interaction potentials that explicitly include sequence information, the phase behavior, energetics, and kinetics of peptide association will be examined. Past work by the productive research collaboration has shown that combining atomically detailed simulations and studies of coarse-grained models has the potential to fully explore the complex problem of amyloid formation. These proposed studies will lead to a conceptual understanding of peptide aggregation, at the molecular level, that is central to the understandingof amyloid diseases.
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