PROTEIN CHEMISTRY CORE

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The "Pathologic Protein Folding and Human Disease" program project application (Program) proposes experimental and computational studies of protein folding and assembly. These studies have relevance to Alzheimer's disease (AD) and other diseases in which pathologic protein folding and aggregation are involved, including Parkinson's, Huntington's, and prion disease. The Peptide Chemistry Core (Core B) will provide chemical synthesis and analysis services to projects 1, 2, 3, and 5. The starting point for the majority of the experimental studies is the amyloid beta-protein (Abeta), which exists in vivo predominately as a 40-42 residue peptide. Core B will synthesize and characterize wild type Abeta peptides and a variety of structurally-related full-length analogues and peptide fragments. Syntheses will be done primarily using automated solid-phase peptide synthesis (SPPS) and FMOC chemistry. Peptide purification will be done using preparative reverse phase HPLC. To characterize the synthetic products, a combination of quantitative amino acid analysis, analytical HPLC, protein sequencing, and mass spectrometry will be used. In addition to direct provision of starting materials and expertise to projects 1, 2, 3, and 5, Core B will synthesize Abeta peptides in which structural modifications will be made to test hypotheses emerging from project 4. Project 4 will utilize in silico approaches to simulate Abeta folding and assembly. These peptides will be provided to the other projects, as appropriate, to perform actual, as opposed to "virtual," experiments. Dr. Teplow (Director) has been involved in the development and application of methods for peptide and protein synthesis, analysis, and study for almost 25 years (1-55). Ms. Condron (Senior Research Associate) is equally experienced in peptide chemistry and instrumentation and has been working with Dr. Teplow for almost 15 years. In addition to the strictly technical contributions of Core B to the Program, Dr. Teplow, Ms. Condron, and other Core B personnel will collaborate with each of the five projects in the design of physical and virtual peptides for hypothesis testing and to address any technical problems that emerge during the execution of the aims of the projects.