464626 Amyloid-β and α-Synuclein: Uncovering Their Commonalities and Differences in Complex with Binding Proteins Using Simulations and Experiments

Friday, November 18, 2016: 12:48 PM
Continental 9 (Hilton San Francisco Union Square)
Asuka A. Orr1, Hamed Shaykhalishahi2, Ewa A. Mirecka2, Wolfgang Hoyer2 and Phanourios Tamamis1, (1)Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX, (2)Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf

Alzheimer’s disease and Parkinson’s disease are the primary neurodegenerative disorders that lead to cognitive and mobility impairment in aging populations (1,2). Amyloid-β peptide (Aβ), and α-synuclein (α-syn) are amyloidogenic proteins that self-assemble and form fibrillar amyloid deposits, pathological features Alzheimer’s disease and Parkinson’s disease, respectively. In Alzheimer’s disease, seline plaques comprise of Αβ proteins, and in Parkinson’s disease Lewy bodies, comprise of α-syn proteins. Interestingly, up to 50% of Alzheimer’s disease cases exhibit the aggregation of α-synuclein into Lewy bodies, associated with a more aggressive disease course, evidence supporting that Aβ and α-syn interact in vivo to promote the aggregation and accumulation of each other and accelerate cognitive dysfunction (3). Thus, the simultaneous inhibition of aggregation by targeting combinations of the two monomeric proteins involved in the aforementioned diseases may constitute a promising therapeutic strategy (4). We have introduced a combination of computational and experimental studies to investigate the two disease-associated amyloidogenic proteins in complex with binding proteins. Using molecular dynamics simulations, free energy calculations (5-8) in CHARMM (9) and in-house structural analysis programs, we have identified the distinct role of energetic driving forces leading to molecular recognition of the two amyloidogenic proteins, Αβ and α-syn, and the key residue interactions with regard to binding and specificity in the framework of the complex formation. Additionally, our computational studies have identified key commonalities and differences of the two disease-associated amyloidogenic proteins in complex with specific protein counterparts. The results of our study suggest possible key determinants for inhibiting Αβ and α-syn and pave the way for the design and discovery of inhibitors as novel potential therapeutic agents.


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