464436 Understanding the Influence of Curcumin on Amyloid-β Aggregation at the Molecular Scale

Monday, November 14, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Tye D. Martin, Center for Biomedical Engineering, University of New Mexico, Albuquerque, NM, David G. Whitten, Center for Biomedical Engineering, Department of Chemical and Biological Engineering, Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM, Eva Y. Chi, Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM and Deborah G. Evans, Department of Chemistry and Chemical Biology, Nanoscience and Microsystems Engineering Program, University of New Mexico, Albuquerque, NM

Alzheimer’s Disease (AD) persists as a threat to the lives of millions in the United States each year, ranking as the sixth leading cause of death among all ages. The disease progression is characterized by the development of highly damaging aggregates in the neuronal network of the brain due to protein misfolding. One of these malfunctioning proteins, Amyloid-β (Aβ), prompts the generation of plaques in the extracellular space of neurons caused by self-assembly of Aβ into insoluble fibrils. It is clear that the fibrils are highly toxic, however the extent of this toxicity continues to be explored. In addition, a number of groups are attempting to understand the aggregation process of Aβ to promote the discovery of chemical agents to interfere with fibril formation. Curcumin, a component of the spice turmeric, is one compound known to alter Aβ assembly. Although once thought to stop fibril formation completely, experimental evidence from studies by our group shows that this compound attenuates the formation of fibrillar Aβ thereby decreasing its toxicity. The molecular scale forces governing the interactions between curcumin and Aβ are hypothesized to stem from hydrophobic effects, but this mechanism is not entirely clear. Theoretical approaches to understanding this process provide a powerful means to investigate how curcumin binds to Aβ fibrils at the molecular scale. We are currently using classical Molecular Dynamics (MD) simulations to study this phenomenon at an atomistic scale with a focus on the critical binding sites and energetics that may be responsible. To this point, we have found multiple locations on short Aβ protofibrils that appear to attract curcumin. Complexation of two or more of these molecules looks to promote the affinity for Aβ as there are multiple locations where dimers of curcumin bind to fibrils after 20 ns.

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