UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
A molecular dynamics study of Amyloid beta peptide structure near lipid bilayers.
Alzheimer?s disease is quickly becoming a major cause of death throughout the world, especially among the elderly population in developed nations. Thus, it is imperative that the causes and early stages of Alzheimer?s disease are clearly understood so that potential treatments and prevention plans can be developed to avert the eventual increase in prevalence of such disorders.
Alzheimer?s disease is neurological disorder that is characterized by the aggregation of misfolded proteins in neurons. For Alzheimer?s disease, one of the prominent aggregate species within neurons is the Amyloid-Beta (A-beta) peptide. Under certain cellular conditions, these unstructured proteins are able to aggregate to form amorphous oligomers or large, structured fibrils identified by their characteristic high beta-sheet content. It was originally believed that these fibrils were the toxic species in neurons but recent research has shifted the focus to amorphous oligomers. These oligomers are predicted to cause neuron death through interrupting cellular trafficking, oxidation of cellular components and creation of non-specific pores in the outer cell membrane. As these small oligomers are one of the potential toxic species in Alzheimer?s disease, a better understanding of the mechanics of forming such oligomers is necessary to understand the progression of the disease.
Previous research has shown that the cell membrane is able to catalyze A-beta aggregation and promote oligomer or fibril formation at A-beta concentrations lower then the aggregation threshold in solution. However, the mechanism by which membranes are able to influence A-beta aggregation is unknown at a molecular level. For this ARRA-funded project, we have used the molecular dynamics computational technique to directly study this interaction at a resolution unavailable to current experimental techniques. The A-beta peptide in solution has previously been a popular system for studies using molecular dynamics, but our work is the first comprehensive study of A-beta/membrane surface interactions using a full atomic description of the system.
In particular, this ARRA-funded project has focused on the interactions of either a single A-beta peptide with the surface of a model lipid bilayer or the interaction of two A-beta peptides, a dimer, with the bilayer surface. The initial aspects of this work focused on the binding of the A-beta peptide to a bilayer, where we observed strong binding regardless of peptide or membrane charge. Next, we performed extensive simulations to show that A-beta did not adopt an ordered structure as a single peptide on the bilayer surface, implying that the beta-structure seen upon aggregation is derived from protein-protein interactions promoted by the bilayer surface. Currently, we are using A-beta dimers to determine if the charge of the bilayer or the dimer structure affects the affinity of the dimer-bilayer interaction. We expect that certain dimer structures will be promoted on specific bilayers and that these dimers, as one of the initial structures in aggregation, will be targets for future therapeutic interventions. Finally, we intend to study the insertion of a single A-beta peptide into a model bilayer. This process is a good approximation for the initial steps in pore formation, thus making this process ideal for future therapeutic intervention as well. We anticipate that a deeper understanding of the A-beta/lipid interactions that occur on the surface of cell membranes will help in the development of pharmaceuticals that can prevent the progression of neuronal cell death that is the hallmark of Alzheimer?s disease.