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

Authors: 
Orr, A. A., 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.

 

1. Alzheimer's Association. Alzheimer's disease facts and figures. Alzheimers Dement. 2011; 7(2) : 208-44.

2. de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006; 5(6) : 525-35.

3. Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM. Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010 May 26; 30(21) : 7281-9.

4. Shaykhalishahi H, Mirecka EA, Gauhar A, Grüning CS, Willbold D, Härd T, Stoldt M, Hoyer W. A β-hairpin-binding protein for three different disease-related amyloidogenic proteins. Chembiochem. 2015; 16(3) : 411-4.

5. Tamamis P, Morikis D, Floudas CA, Archontis G. Species specificity of the complement inhibitor compstatin investigated by all-atom molecular dynamics simulations. Proteins. 2010; 78(12) : 2655-67.

6. Tamamis P, Pierou P, Mytidou C, Floudas CA, Morikis D, Archontis G.Design of a modified mouse protein with ligand binding properties of its human analog by molecular dynamics simulations: the case of C3 inhibition by compstatin. Proteins. 2011; 79(11) : 3166-79.

7. Gorham RD Jr, Forest DL, Tamamis P, López de Victoria A, Kraszni M, Kieslich CA, Banna CD, Bellows-Peterson ML, Larive CK, Floudas CA, Archontis G, Johnson LV, Morikis D. Novel compstatin family peptides inhibit complement activation by drusen-like deposits in human retinal pigmented epithelial cell cultures. Exp Eye Res. 2013; 116 : 96-108.

8. A. Kieslich, Chris; Tamamis, Phanourios; D. Gorham Jr., Ronald; Lopez de Victoria, Aliana; U. Sausman, Noriko; Archontis, Georgios; Morikis, Dimitrios. Exploring Protein-Protein and Protein-Ligand Interactions in the Immune System using Molecular Dynamics and Continuum Electrostatics. Curr Phys Chem. 2012; 2(4) : 324-343(20).

9. Brooks BR, Brooks CL 3rd, Mackerell AD Jr, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M. CHARMM: the biomolecular simulation program. J Comput Chem. 2009; 30(10) : 1545-614.