Alzheimer's disease (AD) is characterized neuropathologically by formation of extracellular amyloid plaques containing the amyloid Beta-protein (ABeta) and intracellular neurofibrillary tangles composed of the protein tau. ABeta self-associates to form amyloid fibrils as bell as smaller, oligomeric assemblies. These aggregation events are thought to underlie the neuronal degeneration and death that produces the profound cerebral atrophy observed in AD. Recent experimental and clinical findings suggest that oligomeric forms of ABeta may be the key neuropathogenetic effectors in AD. It is therefore critical to elucidate the structures of these ABeta oligomers in order to develop pharmaceuticals capable of inhibiting their toxicity. Despite impressive experimental efforts to determine the structures of ABeta oligomers, this goal has not yet been attained. We propose to develop a novel combination of computational tools to determine ABeta oligomeric structures at atomic resolution. These tools include a high-performance simulation technique, discrete molecular dynamics (DMD), and a rapid solvent treatment methodology using all-atom molecular dynamics simulations. We will develop a coarse-grained ab into DMD model of the ABeta peptide which takes into account main-chain hydrogen bond interactions as well as amino acid-specific interactions between side chains.
Our aims will be achieved in collaboration with Dr. D. B. Teplow's group, which has made significant contributions to our understanding of the conformational, morphologic, kinetic, and thermodynamic features of Aft assembly. The in vitro data from Dr. Teplow's studies, as well as those from other groups, will help constrain our model of ABeta oligomer formation. Using this experimentally relevant, coarse-grained model, we will generate a range of candidate oligomeric structures. We then will test the stability of the oligomer conformations using all-atom molecular dynamics simulations and newly-developed methodology for free-energy calculations in an explicit solvent at physiological conditions. The identification of stable structures will allow us to begin to understand the roles specific amino acids play in controlling ABeta assembly. Predictions emanating from these analyses then will be tested experimentally in Dr. Teplow's laboratory through chemical synthesis of appropriate ABeta peptides and study of their assembly and neurotoxic activity.
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