Research Article | Volume: 5, Issue: 3, May-June, 2017

CD and Computational studies on Aβ (1-16) suggests determinants of ligand binding and plausible prevention of metal induced toxicity via Betaine like molecules

Priya Narayan D. Jagadeesh Kumar M. Govinda Raju H. G. Nagendra K. R. K. Easwaran   

Open Access   

Published:  Jun 19, 2017

DOI: 10.7324/JABB.2017.50306

One of the reasons for the plaque formation in Alzheimer’s Disease (AD) is the metal induced aggregation of Aβ(1-42). Its C-terminal hydrophobic residues are generally found inside the membrane; but the exposed regions (1-28) are predominantly ligand interacting and believed to be responsible for onset of aggregation events. Recent evidences have indicated that the smaller fragments of Aβ like (17-28), (1-16) and (1-10) are also produced in presence of secretases and elastase. In this background, the current work focuses upon assessing the binding patterns of the residues contained in the smaller fragments (such as 1-16) with metals like zinc, copper, aluminium, and small molecules like betaine and curcumin, via Circular Dichroism (CD) and computational docking methods. The CD data and in silico exercises offer valuable information about the determinants that take part in ligand binding and thus contribute to the wealth of knowledge towards appreciating the triggering events related to aggregation patterns of AD. These results not only provide insights into the mechanism that underlie the formation of toxic fragments, but also suggest design of molecules that could function as plausible breakers of the progression of Alzheimer’s disease (AD).

Keyword:     Circular DichroismDockingAlzheimers DiseaseA β.


Narayan P, Jagadeesh Kumar D, Govinda Raju M, Nagendra H G, Easwaran KRK. CD and Computational studies on Aβ (1-16) suggests determinants of ligand binding and plausible prevention of metal induced toxicity via Betaine like molecules. J App Biol Biotech. 2017; 5 (03): 030-038. DOI: 10.7324/JABB.2017.50306

Copyright: Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike license.

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1. Bergeron C. Alzheimer’s Disease Neuropathological Aspects. Can J Vet Res. 1990; 54 (1):58–64.

2. Palmer M. Neurochemical Studies of Alzheimer’s Disease. Neurodegeneration. 1996; 5(4): 381–391.

3. Munoz D.G and Feldman H Causes of Alzheimer’s disease. CMAJ. 2000; 162(1): 65–72.

4. Kosik K. S. The Alzheimer’s disease sphinx: a riddle with plaques and tangles. J Cell Biol. 1994; 127(6): 1501–1504.

5. Serpell L. C Alzheimer’s amyloid fibrils: structure and assembly. Biochimica et biophysica acta. 2000; 1502(1):16–30.

6. Barrow C. J, Yasuda A, Kenny PT, Zagorski MG Solution Conformations and Aggregational Properties of Synthetic Amyloid Peptides of Alzheimer’s Disease Analysis of Circular Dichroism Spectra. Journal of molecular biology, 1992; 225(4):1075–1093.

7. Gowing E, Roher A E, Woods A S, Cotter R J, Chaney M, Little S P, Ball M J Chemical characterization of A beta 17-42 peptide, a component of diffuse amyloid deposits of Alzheimer’s disease. The Journal of biological chemistry, 1994; 269(15):10987–90.

8. Damante C A, Ösz K, Nagy Z, Grasso G, Pappalardo G, Rizzarelli E, Sóvágó I. Zn 2+ ’s Ability to Alter the Distribution of Cu 2+ among the Available Binding Sites of Aβ(1-16)-Polyethylenglycol-ylated Peptide: Implications in Alzheimer’s Disease. Inorg Chem. 2011; 50(12): 5342–5350.

9. Lovell M A, Robertson J D, Teesdale W J, Campbell J L, Markesbery W R. Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci. 1998; 158(1):47–52.

10. Bush A.I The metallobiology of Alzheimer’s disease. Trends Neurosci. 2003; 26(4):207–14.

11. Schetinger M.R.C. Bonan C.D. Morsch V.M. Bohrer D. Valentim L.M. and Rodrigues S.R. Effects of aluminum sulfate on delta-aminolevulinatedehydratase from kidney, brain, and liver of adult mice Brazilian Journal of Medical and Biological Research. 1999;(32):761-766.

12. Strozyk D, Launer LJ, Adlard PA, Cherny RA, Tsatsanis A, Volitakis I, Blennow K, Petrovitch H, White LR, Bush AI. Zinc and copper modulate Alzheimer Abetalevels in human cerebrospinal fluid .Neurobiol Aging. 2009; 30(7): 1069-77

13. Ramakrishna T, Vatsala S, Shobi V, Sreekumaran E, Madhav TR, Ramesh J, EaswaranK R K. Betaine reverses toxic effects of aluminium: implications in Alzheimer’s disease (AD) and ADlike pathology. Current Science, 1998; 75(11): 1153–1161.

14. Ramakrishna T, Vatsala S, Madhav TR, Sreekumaran E, Ramesh J, Easwaran KRK. Conformational Change in b-amyloid Peptide [1-40] with Aluminium: Reversal by Borate. Alzheimer’s Research, 1997; 3(5), pp. 223-226.

15. Fasman G. D. Perczel A. and Moore C. D. Solubilization of beta-amyloid-(1-42)-peptide: reversing the beta-sheet conformation induced by aluminum with silicates. Proc Natl Acad Sci U S A, 1995; 92(2):369–71.

16. Curtain C. C. Barnham K. J. and BushA. I. Aβ Metallobiology and the Development of Novel Metal-Protein Attenuating Compounds (MPACs) for Alzheimer’s Disease. Current Medicinal Chemistry, 2003; 3(4): 309–315.

17. Caroline Louis-Jeune, Miguel A. Andrade-Navarro, Carol Perez-Iratxeta Prediction of protein secondary structure from circular dichroism using theoretically derived spectra. Proteins: Structure, Function, and Bioinformatics. 2012; 80(2):374–381.

18. Discovery studio (DS) (Discovery Studio 3.5, Accelrys Inc. San Diego, California, ( USA).

19. Momany, F. A.; Rone, R. J Validation of the general purpose QUANTA 3.2/CHARMm force field. Comp. Chem.1992;(13): 888-900.

20. Krammer A. Kirchhoff P. D. Jiang X. Venkatachalam C. M. Waldman, M.LigScore: a novel scoring function for predicting binding affinities. J. Mol. Graph. Model, 2005; 23: 395-407.

21. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA,Wang J, Yu B, Zhang J, Bryant SH. PubChem Substance and Compound databases. Nucleic Acids Res. 2015; 4(44):1202-13.

22. deZwart, F. Slow, S. Payne, R. L. George, P. Gerrard, J. Chambers, S. Glycine betaine and glycine betaine analogues in common foods. Food Chemistry. 2003; 83: 197 – 204.

23. Mroczkowska JE, Roux FS, Naleçz MJ, Naleçz KA Blood-brain barrier controls carnitine level in the brain: a study on a model system with RBE4 cells . BiochemBiophys Res Commun. 2000;7, 267(1):433-7.

24. Liana Fattore and Walter Fratta Front. Beyond THC: the new generation of cannabinoid designer drugs Front BehavNeurosci. 2011; 5(60):1-12.

25. Narayan P., Krishnarjuna B., Vishwanathan V., Jagadeesh Kumar D., Babu S., Ramanathan KV, Easwaran KRK, Nagendra HG and Raghothama S. Does aluminium bind to histidine? An NMR investigation of amyloid β12 and amyloid β16 fragments, Chem biol drug des. 2013; 82(1): 48–59.

26. Koska J, Spassov VZ, Maynard AJ, Yan L, Austin N, Flook PK, Venkatachalam CM Fully automated molecular mechanics based induced fit protein-ligand docking method .Chem Inf Model. 2008; 48(10): 1965-73.

27. Craig SA. Betaine in human nutrition. Am J ClinNutr. 2004; 80(3): 539-49.

28. Heinzmann SS, Brown IJ, Chan Q, Bictash M, Dumas ME, Kochhar S, Stamler J, Holmes E, Elliott P, Nicholson JK. Metabolic profiling strategy for discovery of nutritional biomarkers: prolinebetaine as a marker of citrus. Am J ClinNutr. 2010; 92: 436–43.

29. Molina M., Ulvena SM, Dahlb L., Telle-Hansena VH, Holcka M., Skjegstada G., Ledsaaka O., Slothb JJ, Goesslerd W, Oshauga A, Alexandere J, Fliegelb D, Ydersbondf TA, Meltzere HM. Humans seem to produce arsenobetaine and dimethylarsinate after a bolus dose of seafood Environmental Research. 2012; 112: 28–39.

30. John S. Edmonds, Kevin A. Francesconi, Jack R. Cannon, Colin L. Raston, Brian W. Skelton and Allan H. White. Isolation, crystal structure and synthesis of arsenobetaine, the arsenical constituent of the western rock lobster panuliruslongipescygnus George. Tetrahedron Letters. 1997; 18:1543–1546.

31. Zhou J1, Chan L, Zhou S, Trigonelline: a plant alkaloid with therapeutic potential for diabetes and central nervous system disease Curr Med Chem. 2012; 19(21):3523-31.

32. Duane C. Yoch Dimethylsulfoniopropionate: Its Sources, Role in the Marine Food Web, and Biological Degradation to Dimethylsulfide. Appl. Environ. Microbiol,2002; 68(12):5804-5815.

33. ChenY. R. HuangH. B. Chyan C. L. Shiao M. S. LinT. H. and Chen Y. C. The effect of Abeta conformation on the metal affinity and aggregation mechanism studied by circular dichroism spectroscopy, J Biochem. 2006; 139(4):733–40.

34. Syme C. D. Nadal R. C. Rigby S. E. J. and Viles J. H. Copper binding to the amyloid-beta (Abeta) peptide associated with Alzheimer’s disease: folding, coordination geometry, pH dependence, stoichiometry, and affinity of Abeta-(1- 28): insights from a range of complementary spectroscopic techniques. J Biol Chem. 2004: 279(18): 18169–77.

35. Syme C. D. and Viles J. H. ‘Solution 1H NMR investigation of Zn2+ and Cd2+ binding to amyloid-beta peptide (Abeta) of Alzheimer’s disease. BiochimBiophysActa. 2006; 1764(2): 246–56.

36. Alok Vyas, Prasad Dandawate, Subhash Padhye, Aamir Ahmad, and Fazlul Sarkar Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties Curr Pharm Des. 2013;19(11):2047–2069.

37. Owen RT,Memantine and donepezil: a fixed drug combination for the treatment of moderate to severe Alzheimer's dementia, Drugs Today (Barc), 2016,52(4):239-48.

38. Buckley JS, Salpeter SR A Risk-Benefit Assessment of Dementia Medications: Systematic Review of the Evidence. Drugs Aging, 2015; 32(6):453-67.

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