Design and Characterization of Alpha-Sheet Compounds

University Of Washington, Seattle WA

Investigators

Abstract

0966977 Daggett Intellectual Merits: Some years ago a novel protein secondary structure was "discovered" by computer simulations of amyloidogenic proteins. Interestingly, this structure, á-sheet, was initially predicted by Pauling and Corey in 1951. This structure is observed under amyloidogenic conditions but not under normal conditions. The structure is adopted in a variety of proteins with completely different starting, biologically active conformations. This structure is proposed to represent a generic toxic amyloidogenic structure. This proposal seeks to design small stable á-sheets to characterize their properties biophysically, including directly determining the structure using experimental techniques. Furthermore, the designs will be tested for their ability to prevent amyloid formation in the protein transthyretin (and formerly known as prealbumin) and to preferentially bind the toxic form of the protein because of its complementarity. The proposal marries computational and experimental approaches to take a prediction from simulation and prove that the structure exists and corresponds to a state of critical importance to human disease. Broader Impact: The results from this study will be published in peer-reviewed high-quality science journals. In addition, the work will be presented in a less technical form on the Daggett Group website. Since the work makes use of the Dynameomics Database for peptide design, the results will also be featured at www.dynameomics.org. This site receives about 500 hits a day from around the world. Both undergraduate and graduate students will be encouraged to articipate in the project. Given that the project contains both computational and experimental components, it provides broad training potential. Those involved in the computational work will have the opportunity to use a government high performance computing facility. There are also potentially broad implications to the proposed research for human health. The research should provide fundamental information critical to the future development of diagnostic and therapeutic agents for amyloid diseases. As the demographics shift and our population ages, amyloid diseases are on the rise and Alzheimer's disease alone is projected to reach epidemic proportions in the next 5 years. For most of these diseases there is no cure and no way to diagnose the disease aside from an autopsy. While the work proposed here is more basic, the á-sheet idea is novel and may provides another route to attack these problems, which is desirable since the conventional approaches have made little headway. In addition, there is increasing interest in using amyloids as biomaterials for a variety of nanotechnology, including biomedical, applications. Here it is very desirable to have more information about toxic species addressed in this proposal so that they can be avoided.