DESCRIPTION (provided by applicant): This proposal is a request to continue highly productive research elucidating the fundamental principles underlying amyloid protein association and aggregation, linked to Alzheimer's Disease and other neurodegenerative disorders. The long-term goal is the formulation of the fundamental principles of polypeptide association and fibril formation, key to our understanding of amyloid disease. As a result of evidence suggesting that soluble low molecular weight (LMW) aggregates of amyloidogenic proteins are the primary cause of neurotoxicity, it has become urgent to understand the molecular mechanisms of formation of LMW oligomers. It is also necessary to explore the nature of external conditions, including pH, denaturant, and temperature that can drive conformational fluctuations in monomeric peptides making them prone to aggregation. 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 Amyloid beta-peptides, linked to Alzheimer's Disease, and human amylin, whose aggregation is implicated in type II diabetes. The effort has four specific aims: (1) Employ all-atom molecular dynamics simulations to probe the effects of sequence variations in the aggregation of Amyloid beta-peptides. These studies will map the assembly pathways in these peptides and provide a molecular-level understanding of the variations in observed fibrillization rates among naturally occurring Amyloid beta-peptide mutants. (2) Explore the factors that contribute to the stability of oligomers of Amyloid beta-peptides, and the response of interacting Ap-peptides to the denaturant urea. (3) Complete computational studies on why human amylin aggregates, while amylin from rats does not. Comparison of results for Amyloid beta and amylin peptides will provide a conceptual framework for understanding sequence and environmental effects on association of peptides and proteins. (4) Discover the general principles of polypeptide association. Detailed molecular dynamics simulations will be supplemented with coarse-grained off-lattice models of polypeptides. Employing such 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 this productive research collaboration has shown that a blend of atomically detailed simulations and studies of coarse-grained models is necessary to fully explore the complex problem of protein aggregation and amyloid formation. Relevance to Public Health. The proposed investigations will advance the study of the aggregation and reorganization of the amyloid p-peptide, implicated in Alzheimer's Disease, and other neurodegenerative disorders, as well as elucidate the factors that influence the formation of amylin polypeptide aggregates, implicated in type II diabetes.