AB INITIIO MOLECULAR DYNAMICS OF AB FOLDING AND ASSEMBLY

University Of California Los Angeles, Los Angeles CA

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Abstract

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