Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol
Molecular dynamic (MD) simulation is an approach frequently employed in computational biology for exhaustive sampling of the protein-ligand conformational space. Hence, it is useful for structural analysis and the study of molecular interactions. In this study, we report on a MD simulation protocol to understand the dynamics of β-secretase 1 (BACE1) and 2 (BACE2), widely known to play a critical role in the etiology of Alzheimer’s disease, by a structure change evaluation of their transmembrane domains while inserted in a simulated neural membrane system. We considered two different levels in membrane cholesterol content. Because there is no evidence supporting the capacity of BACE1 and BACE2 to exist as a dimer, single and double (BACE1/BACE1, BACE2/BACE2, BACE1/BACE2) systems, either in parallel or antiparallel orientation, were prepared for each run. Analysis of tridimensional structure of BACE1 and BACE2, after 10ns of MD simulation, revealed a correlation between higher cholesterol levels and both peptide refolding and changes in the secondary structure of both transmembrane domains in single and double systems. Interestingly, our results also indicate a potential interaction in the double system BACE2/BACE2, particularly when the domains had an antiparallel orientation.
J. Cummings, “What can be inferred from the interruption of the semagacestat trial for treatment of alzheimer’s disease?” Biol. Psychiatry, vol. 68, no. 10, November 15 2010. [Online]. Available: https://doi.org/10.1016/j.biopsych.2010.09.020
M. Prince and et al., “World alzheimer report 2015 the global impact of dementia,” Alzheimer’s Dis. Int., London, United Kingdom, Tech. Rep., Aug. 2015.
G. Koelsch, “BACE1 function and inhibition: Implications of intervention in the amyloid pathway of alzheimer’s disease pathology,” Molecules, vol. 22, no. 10, October 13 2017. [Online]. Available: https://doi.org/10.3390/molecules22101723
J. Mendiola, L. C. Berumen, K. Padilla, and G. Garcia, “Therapies for prevention and treatment of alzheimer’s disease,” Biomed Res. Int., vol. 2016, 2016. [Online]. Available: https://doi.org/10.1155/2016/ 2589276
R. Yan and R. Vassar, “Targeting the β secretase BACE1 for alzheimer’s disease therapy,” Lancet Neurol., vol. 13, no. 3, March 2014. [Online]. Available: https://doi.org/10.1016/S1474-4422(13) 70276-X
A. K. Dhanabalan, M. Kesherwani, D. Velmurugan, and K. Gunasekaran, “Identification of new BACE1 inhibitors using pharmacophore and molecular dynamics simulations approach,” J.Mol. Graph. Model., vol. 76, September 2017. [Online]. Available: https://doi.org/10.1016/j.jmgm.2017.06.001
J. H. Stockley and C. O’Neill, “The proteins BACE1 and BACE2 and beta-secretase activity in normal and alzheimer’s disease brain,” Biochemical Society transactions, vol. 35, pp. 574–576, Jun. 2007.
M. Stefani and G. Liguri, “Cholesterol in alzheimer’s disease: unresolved questions,” Curr. Alzheimer Res., vol. 6, no. 1, pp. 15–29, Feb. 2009.
W. Ye, W. Wang, C. Jiang, Q. Yu, and H. Chen, “Molecular dynamics simulations of amyloid fibrils: an in silico approach,” Acta Biochim. Biophys. Sin., vol. 45, no. 6, June 2013. [Online]. Available: https://doi.org/10.1093/abbs/gmt026
A. Lamiable and et al., “PEP-FOLD3: faster de novo structure prediction for linear peptides in solution and in complex,” Nucleic Acids Res., vol. 44, July 08 2016. [Online]. Available: https: //doi.org/10.1093/nar/gkw329
M. Hernández, M. C. Rosales, J. E. Mendieta, M. M. Archundia, and J. Correa, “Current tools and methods in molecular dynamics (MD) simulations for drug design,” Current Medicinal Chemistry,, vol. 23, May 2016. [Online]. Available: https://doi.org/10.2174/ 0929867323666160530144742
P. Gamba and et al., “The link between altered cholesterol metabolism and alzheimer’s disease,” Ann. N. Y. Acad. Sci., vol. 1259, July 2012. [Online]. Available: https://doi.org/10.1111/j. 1749-6632.2012.06513.x
P. Derreumaux, “From polypeptide sequences to structures using monte carlo simulations and an optimized potential,” J. Chem. Phys., vol. 111, no. 5, July 20 1999. [Online]. Available: https: //doi.org/10.1063/1.479501
A. Allouche, “Gabedit-a graphical user interface for computational chemistry softwares,” J. Comput. Chem., vol. 32, no. 1, January 2011. [Online]. Available: https://doi.org/10.1002/jcc.21600
M. A. Barrett, R. J. Alsop, T. Hauß, and M. C. Rheinstädter, “The position of aβ22−40 and aβ1−42 in anionic lipid membranes containing cholesterol,” Membranes (Basel)., vol. 5, no. 4, December 2015. [Online]. Available: https://doi.org/10.3390/membranes5040824
V. D. Spoel, “GROMACS: fast, flexible, and free,” J. Comput. Chem., vol. 26, no. 16, pp. 1701–1718, Dec. 2005.
M. J. Abraham and et al., “GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers,” Software X, vol. 1-2, September 2015. [Online]. Available: https://doi.org/10.1016/j.softx.2015.06.001
S. L. Cole and R. Vassar, “BACE1 structure and function in health and alzheimer’s disease,” Curr. Alzheimer Res., vol. 5, no. 2, April 2008. [Online]. Available: https://doi.org/10.2174/156720508783954758
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