A molecular dynamics study of Amyloid Beta peptide structure near lipid bilayers

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Neurodegenerative disorders are a major cause of sickness and death throughout the world. Many of these disorders represent a class of protein aggregation diseases wherein small misfolded proteins aggregate and lead to deteriorating cellular function. To determine appropriate treatments and potential cures for these disorders, it is imperative to understand the mechanism by which proteins misfold and aggregate. The long- term research goal of this work is to identify factors in aged neurons that promote formation of toxic structures common to aggregation disorders, in particular Alzheimer's disease. In Alzheimer's disease, the Amyloid Beta (A Beta) peptide is the probable aggregate species. In experiments, A Beta does not aggregate at low peptide concentrations, but the addition of lipids as vesicles or bilayers to a low concentration of A Beta peptides leads to aggregation. To better understand the mechanism by which lipids influence A Beta aggregation, the objective of this proposal is to determine if lipid bilayers stimulate aggregation by directly promoting a conversion to a fibril-like morphology in peptides. We hypothesize that conversion of A Beta peptides to Beta-sheet structure characteristic of fibrils is (1) directly influenced by electrostatic interactions with the surface of anionic lipid bilayers and (2) promoted by interactions with the surface of rigid, cholesterol-rich lipid rafts. We also hypothesize that bilayers of high cholesterol content promote fibril formation by preventing A Beta insertion into the bilayer, which sequesters A Beta from the pool of soluble peptides available for aggregation. In specific aim 1, molecular dynamics (MD) simulations will be used to determine if the charge of lipid headgroups influence A Beta structure and binding free energies near the membrane surface. In specific aim 2, MD simulations will ascertain, by free energy and secondary structure calculations, if bilayer rigidity affects interactions between A Beta and the surface of binary lipid/cholesterol mixtures of varying cholesterol content. In specific aim 3, both the free energy of insertion of A Beta into bilayers and the free energy of two peptides associating within bilayers of varying cholesterol content will be calculated from MD simulations, which will provide insight into potential pore formation by A Beta. The results of this work will provide details on a single peptide level to determine the role of membranes in the A Beta aggregation pathway. Using these results, coupled with experimental work on A Beta aggregation, a clearer description of A Beta aggregation and its function in neuron toxicity in Alzheimer's disease can be used to develop treatments to either halt the progression or possibly prevent and cure one of the most lethal neurodegenerative disorders, Alzheimer's disease.