(781b) Amyloid-β and α-Synuclein: Uncovering Their Commonalities and Differences in Complex with Binding Proteins Using Simulations and Experiments | AIChE

(781b) Amyloid-β and α-Synuclein: Uncovering Their Commonalities and Differences in Complex with Binding Proteins Using Simulations and Experiments


Orr, A. A. - Presenter, Texas A&M University
Shaykhalishahi, H., Heinrich-Heine-Universität Düsseldorf
Mirecka, E. A., Heinrich-Heine-Universita? Düsseldorf
Hoyer, W., Heinrich-Heine-Universita? Düsseldorf
Tamamis, P., TAMU
Alzheimerâ??s disease and Parkinsonâ??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 Alzheimerâ??s disease and Parkinsonâ??s disease, respectively. In Alzheimerâ??s disease, seline plaques comprise of Î?β proteins, and in Parkinsonâ??s disease Lewy bodies, comprise of α-syn proteins. Interestingly, up to 50% of Alzheimerâ??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, Î?β 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 Î?β and α-syn and pave the way for the design and discovery of inhibitors as novel potential therapeutic agents.


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