AB INITIIO MOLECULAR DYNAMICS OF AB FOLDING AND ASSEMBLY

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The amyloid beta protein (Abeta) has been strongly linked to the etiology and pathogenesis of Alzheimer's disease (AD). Abeta assembles into amyloid fibrils and smaller, oligomeric assemblies. We hypothesize that Abeta assembly leads to neuronal injury and cell death, producing the profound cerebral atrophy observed in AD. Experimental and clinical findings suggest that oligomeric forms of Abeta may be particularly important. If so, elucidation of the structures of these Abeta oligomers and the mechanisms of their formation will be critical for developing therapeutic agents. Despite impressive experimental studies of the structures and dynamics of Abeta assembly, a full understanding has not been obtained. We propose to incorporate an in silico approach into a systematic strategy for understanding Abeta assembly and its neurotoxic effects. This strategy involves a feedback <-> feedforward collaboration between our in silico and other in vitro projects in the program project grant. Our computational tools allow for examination of 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. Coarse-grain ab initio DMD models of Abeta have been developed that take 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 the Teplow, the Bitan, the Benedek, and the Bowers-Shea groups, which have made significant contributions to our understanding of the conformational, morphologic, kinetic, and thermodynamic features of Abeta assembly. The in vitro data from these studies, as well as those from other groups, will help guide development of the first-generation DMD approach to model Abeta folding and oligomer formation. Using this first-generation DMD approach, we will generate a range of candidate oligomeric structures (conformers). We will then test the stability of these conformers using all-atom molecular dynamics simulations in explicit solvent at physiological conditions. After identifying the most stable conformers, we will formulate hypotheses about which amino acids and interactions play the key roles in folding and assembly. These hypotheses will be tested in vitro by the other groups in this program. The results of these in vitro findings will be "fed back" into the DMD approach and will provide means to develop the second-generation DMD approach. We will then seek, in collaboration with the other groups in the program, to select potentially toxic conformers. In addition, we will develop in silico screening methodology to study mixtures of Abeta42 (or any other peptide) with a potential oligomerization inhibitor, such as a C-terminal fragment of Abeta42. The outcome of these studies will be a series of peptide inhibitors of potential use in drug development to prevent Abeta oligomer formation.