Metal-Peptide and Peptide-Peptide Interactions of Relevance to Alzheimer's Disease

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Alzheimer's disease(AD) is caused by an aggregated form of the amyloid beta peptide (Ab, or Ab(1-42)) in association with metals ions, primarily, Cu2+/Cu1+, Zn2+, Fe3+/Fe2+, ferro- and ferriheme. The overall objective is to determine the chemical causes or propagating steps of AD. The immediate objectives for the next granting period build on previous work and address some important as yet unanswered questions. All are in the realm of basic physical and computational chemistry applied to processes of biological interest. The proposed research directly addresses the structure and redox properties of Cu and Fe(heme)/Ab complexes. These generate reactive oxygen species (ROS) that in bological systems cause damage to cell components. We also address the interactions between Ab and peptides/pseudopeptides, and proteins that bind to it, with the aim of determining binding affinities and sequence specificities. We will also simulate the nature of neuronal and endothelial membranes, and the chemical and physical interactions between them and Ab that result in lipid peroxidation and pore formation.