Current Science

Open Access Open Access  Restricted Access Subscription Access

A Comparative Study to Elucidate the Inhibitory Mechanism of a 6-Mer Fragment of Amyloid-Beta 42 Peptide as a Potential Therapeutic in Alzheimer’s Disease:Insights from Molecular Dynamics Simulations


Affiliations
1 Department of Molecular Biology and Biotechnology, Tezpur University, Sonitpur 784 028, India
 

Alzheimer’s disease is a neurodegenerative and incurable disease that is associated with the amyloid beta (Aβ) aggregation. We have carried out comparative molecular dynamics simulations of a 6-mer peptide and its analogues to elucidate the inhibitory mechanism on Aβ aggregation. The top analogue screened after refinement via docking exhibited significant inhibitory activities on both Aβ17–42 fibril as well as Aβ1–42 monomer, leading to disassembly of β-strands of Aβ1–42 peptide and fibril by interacting with C-terminal residues via hydrogen bonds and hydrophobic contacts. Binding of the analogue to the C-terminal region proves to be significant.

Keywords

Alzheimer’s Disease, Aggregation, Docking, Hydrophobic Interaction, Inhibitor Peptide.
User
Notifications
Font Size

  • Tan, S. Y., Pepys, M. B. and Hawkins, P. N., Treatment of amyloidosis. Am. J. Kidney Dis., 1995, 26, 267–285.

  • Tyco, R., Progress towards a molecular-level structural understanding of amyloid fibrils. Curr. Opin. Struct. Biol., 2004, 14, 96–103.

  • Selkoe, D. J., Alzheimer’s Disease: genotypes, phenotype, and treatments. Science, 1977, 275, 630−631.

  • Haass, C. and Selkoe, D. J., Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell, 1993, 75, 1039–1042.

  • Tycko, R., Molecular structure of amyloid fibrils: insights from solid-state NMR. Q. Rev. Biophys., 2006, 39, 1–55.

  • Torok, M., Milton, S., Kayed, R., Wu, P., McIntire, T., Glabe, C. G. and Langen, R., Structural and dynamic features of Alzheimer’s Aβ peptide in amyloid fibrils studied by site-directed spin labeling. J. Biol. Chem., 2002, 277, 40810–40815.

  • Sarkar, N., Kumar, M. and Dubey, V. K., Effect of sodium tetrathionate on amyloid fibril: Insight into the role of disulfide bond in amyloid progression. Biochimie, 2011, 93, 962–968.

  • Hard, T. and Lendel, C., Inhibition of amyloid formation. J. Mol. Biol., 2012, 424, 441–465.

  • Liu, R., Su, R., Liang, M., Huang, R., Wang, M., Qi, W. and He, Z., Physicochemical strategies for inhibition of amyloid fibril formation: an overview of recent advances. Curr. Med. Chem., 2012, 19, 4157–4174.

  • Sarkar, N., Kumar, M. and Dubey, V. K., Rottlerin dissolves preformed protein amyloid: a study on hen egg white lysozyme. BBAGen. Subjects, 2011, 1810, 809–814.

  • Lannfelt, L. et al., Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer’s disease: A phase IIa, double-blind, randomised, placebocontrolled trial. Lancet Neurol., 2008, 7, 779–786.

  • Yang, F. S. et al., Curcumin inhibits formation of amyloid-β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem., 2005, 280, 5892–5901.

  • Nakagami, Y., Nishimura, S., Murasugi, T., Kaneko, I., Meguro, M., Marumoto, S., Kogen, H., Koyama, K. and Oda, T., A novel β-sheet breaker, RS-0406, reverses amyloid β-induced cytotoxicity and impairment of long-term potentiation in vitro. Br. J. Pharmacol., 2002, 137, 676–682.

  • Porat, Y., Abramowitz, A. and Gazit, E., Inhibition of amyloid fibril formation by polyphenols: Structural similarity and aromatic interactions as a common inhibition mechanism. Chem. Biol. Drug. Des., 2006, 67, 27–37.

  • Chacon, M. A., Barria, M. I., Soto, C. and Inestrosa, N. C., β-sheet breaker peptide prevents A -induced spatial memory impairments with partial reduction of amyloid deposits. Mol. Psychiatry., 2004, 9, 953–961.

  • Gordon, D. J., Sciarretta, K. L. and Meredith, S. C., Inhibition of Aβ1−40 fibrillogenesis and disassembly of Aβ1–40 fibrils by short  -amyloid congeners containing N-methyl amino acids at alternate residues. Biochemistry, 2001, 40, 8237−8245.

  • Grillo-Bosch, D. et al., Retro-enantio N-methylated peptides as-amyloid aggregation inhibitors. ChemMedChem., 2009, 4, 1488–1494.

  • Granic, I. et al., Leu-Pro-Tyr-Phe-Asp-NH2 neutralizes Aβ induced memory impairment and toxicity. J. Alzheimers Dis., 2010, 19, 991–1005.

  • Kokkoni, N., Stott, K., Amijee, H., Mason, J. M. and Doig, A. J., N-Methylated analogues of β-amyloid aggregation and toxicity: Optimization of the inhibitor structure. Biochemistry, 2006, 45, 9906–9918.

  • Matharu, B., El-Agnaf, O., Razvi, A. and Austen, B. M., Development of retro-inverso peptides as anti-aggregation drugs for β amyloid in Alzheimer’s disease. Peptides, 2010, 31, 1866–1872.

  • Carter, M. D., Simms, G. A. and Weaver, D. F., The development of new therapeutics for Alzheimer’s disease. Clin. Pharmacol. Ther., 2010, 88, 475–486.

  • Fradinger, E. A. et al., C-Terminal peptides co-assemble into Aβ1−42 oligomers and protect neurons against Aβ1–42-induced neurotoxicity. Proc. Natl. Acad. Sci. USA, 2008, 105, 14175–14180.

  • Pratim Bose, P. et al., Poly-N-methylated amyloid β-peptide (Aβ) C-terminal fragments reduce Aβ toxicity in vitro and in Drosophila melanogaster. J. Med. Chem., 2009, 52, 8002–8009.

  • Hilbich, C., Kisters-Woike, B., Reed, J., Masters, C. L. and Beyreuther, K., Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer’s disease A peptides. J. Mol. Biol., 1992, 228, 460–473.

  • Jarrett, J. T., Berger, E. P. and Lansbury Jr, P. T., The carboxy terminus of the amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer’s disease? Biochemistry, 1993, 32, 4693–4697.

  • Bansal, S., Maurya, I. K., Yadav, N., Thota, C. K., Kumar, V., Tikoo, K. and Jain, R., C-Terminal fragment, Aβ32–37, analogues protect against Aβ aggregation-induced toxicity. ACS Chem. Neurosci., 2016, 7, 615–623.

  • Kirkwood, J. G., Statistical mechanics of fluid mixtures. J. Chem. Phys., 1935, 3, 300–313.

  • Torrie, G. M. and Valleau, J. P., Monte Carlo free energy estimates using non-Boltzmann sampling: application to the sub-critical Lennard–Jones fluid. Chem. Phys. Lett., 1974, 28, 578–581.

  • Crescenzi, O., Tomaselli, S., Guerrini, R., Salvadori, S., D’Ursi, A. M., Temussi, P. A. and Picone, D., Solution structure of the Alzheimer amyloid β‐peptide (1–42) in an apolar microenvironment. Eur. J. Biochem., 2002, 22, 5642–5648.

  • Westbrook, J., Feng, Z., Chen, L., Yang, H. and Berman, H. M., The protein data bank and structural genomics. Nucleic Acids Res., 2003, 31, 489–491.

  • Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. and Klein, M. L., Comparison of simple potential functions for simulating liquid water. J. Chem. Phys., 1983, 79, 926–935.

  • Case, D. A. et al., AMBER 12, 2012; http://ambermd.org/doc12/Amber12.pdf

  • Lindorff‐Larsen, K., Piana, S., Palmo, K., Maragakis, P., Klepeis, J. L., Dror, R. O. and Shaw, D. E., Improved side‐chain torsion potentials for the Amber ff99SB protein force field. Proteins: Struct. Funct. Bioinf., 2010, 78, 1950–1958.

  • Berendsen, H. J., Postma, J. V., van Gunsteren, W. F., DiNola, A. R. and Haak, J. R., Molecular dynamics with coupling to an external bath. J. Chem. Phys., 1984, 81, 3684–3690.

  • Ryckaert, J. P., Ciccotti, G. and Berendsen, H. J., Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys., 1977, 23, 327–341.

  • Darden, T., York, D. and Pedersen, L., Particle mesh Ewald: An N-log (N) method for Ewald sums in large systems. J. Chem. Phys., 1993, 98, 10089–10092.

  • DeLano, W. L., The PyMOL Molecular Graphics System, Version 1, DeLano Scientific, Palo Alto, CA, 2002.

  • Guex, N. and Peitsch, M. C., SWISS‐MODEL and the Swiss‐Pdb Viewer: an environment for comparative protein modeling. Electrophoresis, 1997, 18, 2714–2723.

  • Luhrs, T., Ritter, C., Adrian, M., Loher, B., Bohrmann, D. R., Dobeli, H., Schubert, D. and Riek, R., 3D structure of Alzheimers amyloid-β (1–42) fibrils. Proc. Natl. Acad. Sci. USA, 2005, 102, 17342–17347.

  • Schneidman-Duhovny, D., Inbar, Y., Nussinov, R. and Wolfson, H. J., PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res., 2005, 33, W363–W367.

  • Kumar, S., Bouzida, D., Swendsen, R. H., Kollman, P. A. and Rosenberg, J. M., The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J. Comput. Chem., 1992, 13, 1011–1021.

  • Humphrey, W., Dalke, A. and Schulten, K., VMD: visual molecular dynamics. J. Mol. Graph., 1996, 14, 33–38.

  • Sobolev, V., Eyal, E., Gerzon, S., Potapov, V., Babor, M., Prilusky, J. and Edelman, M., SPACE: a suite of tools for protein structure prediction and analysis based on complementarity and environment. Nucleic Acids Res., 2005, 33, W39–W43.

  • Laskowski, R. A., PDBsum: summaries and analyses of PDB structures. Nucleic Acids Res., 2001, 29, 221–222.


Abstract Views: 383

PDF Views: 114




  • A Comparative Study to Elucidate the Inhibitory Mechanism of a 6-Mer Fragment of Amyloid-Beta 42 Peptide as a Potential Therapeutic in Alzheimer’s Disease:Insights from Molecular Dynamics Simulations

Abstract Views: 383  |  PDF Views: 114

Authors

Mary Dutta
Department of Molecular Biology and Biotechnology, Tezpur University, Sonitpur 784 028, India
Venkata Satish Kumar Mattaparthi
Department of Molecular Biology and Biotechnology, Tezpur University, Sonitpur 784 028, India

Abstract


Alzheimer’s disease is a neurodegenerative and incurable disease that is associated with the amyloid beta (Aβ) aggregation. We have carried out comparative molecular dynamics simulations of a 6-mer peptide and its analogues to elucidate the inhibitory mechanism on Aβ aggregation. The top analogue screened after refinement via docking exhibited significant inhibitory activities on both Aβ17–42 fibril as well as Aβ1–42 monomer, leading to disassembly of β-strands of Aβ1–42 peptide and fibril by interacting with C-terminal residues via hydrogen bonds and hydrophobic contacts. Binding of the analogue to the C-terminal region proves to be significant.

Keywords


Alzheimer’s Disease, Aggregation, Docking, Hydrophobic Interaction, Inhibitor Peptide.

References





DOI: https://doi.org/10.18520/cs%2Fv114%2Fi06%2F1207-1213