Contributions of Hydrophobic Residues into Thermodynamics and Kinetics of Amyloid

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DESCRIPTION (provided by applicant): One of the characteristics of Alzheimer's disease is the presence of neurotoxic deposits in brain tissues, which are largely made up of a short peptide referred to as A?. The elucidation of the factors responsible for the formation and stabilization of pathologically relevant fibrils is important for designing preventive and therapeutic agents to combat the disease. We aim to investigate one specific aspect of the fibril stabilization process as part of the overall fibril stability picture, namely the role of individua non-polar side chains located in the hydrophobic interior of the fibrils. Thus, our studies will complement global investigations into stability by revealing the most important local sites, which can then become targets for the design of modifications, ligands, and mutants that disrupt the stabilization of the fibrils. Our tools will allow for a balanced view of kinetic and thermodynamic stabilization at the selected sites. We will study two different morphologies of the wild-type peptide as well as a mutant associated with the early onset of the disease. We will utilize deuterium nuclear magnetic resonance spectroscopy and computational modeling to achieve this goal.