In silico Probing Ca2+ And Zn2+ Permeable Transmembrane 4Aβ1-42 Barrel

Son Tung Ngo


Alzheimer’s disease is known as one of the most popular forms of dementia affecting numerous people worldwide. The Amyloid beta (Aβ) peptides form to oligomeric conformations that cause the intracellular Ca2+ and Zn2+ abnormality leading to the death of neuron cells. The failure of AD therapy targeting Aβ oligomers probably caused by misunderstanding the ions transport through transmembrane Aβ (tmAβ) ion-like channel since Aβ oligomers transiently exist in a mixture order of Aβ oligomers. The high-resolution of tmAβ peptides are thus unavailable until the date. Fortunately, computational approaches are able to complement the missing experimental structures. The transmembrane 4Aβ1-42 (tm4Aβ1-42) barrel, one of the most neurotoxic elements, was thus predicted in the previous work. Therefore, in this context, the Ca2+/Zn2+ ions transport through the tm4Aβ1-42 barrel was investigated by using the fast pulling of ligand (FPL) and umbrella sampling (US) methods. Good consistent results were obtained implying that Ca2+ ion transport through tm4Aβ1-42 barrel with a lower free energy barrier compared with Zn2+ ion. The obtained results about Ca2+/Zn2+ transport across tm1-42 barrel probably enhances the AD therapy


Amyloid, Ion channel, tetramer barrel, US, FPL, Ca2+, Zn2+

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Selkoe, D.J. The Molecular Pathology of Alzheimer's Disease. Neuron, 6 (1991) 487-98.

Querfurth, H.W., LaFerla, F.M. Alzheimer's disease. N. Engl. J. Med., 362 (2010) 329-44.

Selkoe, D.J., Hardy, J. The Amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med., 8 (2016) 595-608.

Bitan, G., Kirkitadze, M.D., Lomakin, A., Vollers, S.S., Benedek, G.B., Teplow, D.B. Amyloid β-Protein (Aβ) Assembly: Aβ40 and Aβ42 Oligomerize through Distinct Pathways. Proc. Natl. Acad. Sci. U.S.A., 100 (2003) 330-5.

Kirkitadze, M.D., Condron, M.M., Teplow, D.B. Identification and Characterization of Key Kinetic Intermediates in Amyloid β-Protein Fibrillogenesis. J. Mol. Biol., 312 (2001) 1103-19.

Ngo, S.T., Hung, H.M., Truong, D.T., Nguyen, M.T. Replica Exchange Molecular Dynamics Study of the Truncated Amyloid Beta (11-40) Trimer in Solution. Phys. Chem. Chem. Phys., 19 (2017) 1909-19.

Ngo, S.T., Luu, X.-C., Nguyen, M.T., Le, C.N., Vu, V.V. In silico studies of solvated F19W amyloid β (11-40) trimer. RSC Advances, 7 (2017) 42379-86.

Ngo, S.T., Truong, D.T., Tam, N.M., Nguyen, M.T. EGCG Inhibits the Oligomerization of Amyloid Beta (16-22) Hexamer: Theoretical Studies. J. Mol. Graph. Model., 76 (2017) 1-10.

Jarvis, L.M. Clinical Trial Failures. Chem. Eng. News, 90 (2012) 8.

Abbott, A., Dolgin, E. Failed Alzheimer's Trial does not Kill Leading Theory of Disease. Nature, 540 (2016) 15-6.

Panza, F., Solfrizzi, V., Imbimbo, B.P., Logroscino, G. Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: the point of no return? Expert Opin Biol Ther, 14 (2014) 1465-76.

Rosenblum, W.I. Why Alzheimer trials fail: removing soluble oligomeric beta amyloid is essential, inconsistent, and difficult. Neurobiol Aging, 35 (969-74.

Doig, A.J., del Castillo-Frias, M.P., Berthoumieu, O., Tarus, B., Nasica-Labouze, J., Sterpone, F., et al. Why Is Research on Amyloid-β Failing to Give New Drugs for Alzheimer’s Disease? ACS Chem Neurosci, 8 (2017) 1435-7.

Lal, R., Lin, H., Quist, A.P. Amyloid beta ion channel: 3D structure and relevance to amyloid channel paradigm. BBA - Biomembranes, 1768 (2007) 1966-75.

Connelly, L., Jang, H., Teran Arce, F., Capone, R., Kotler, S.A., Ramachandran, S., et al. Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-d-Enantiomer of Alzheimer’s β-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology. J. Phys. Chem. B, 116 (2012) 1728-35.

Ngo, S.T., Derreumaux, P., Vu, V.V. Probable Transmembrane Amyloid α-Helix Bundles Capable of Conducting Ca2+ Ions. J. Phys. Chem. B, 123 (2019) 2645–53.

Nguyen, P.H., Campanera, J.M., Ngo, S.T., Loquet, A., Derreumaux, P. Tetrameric Aβ40 and Aβ42 β-Barrel Structures by Extensive Atomistic Simulations. I. In a Bilayer Mimicking a Neuronal Membrane. J. Phys. Chem. B, 123 (2019) 3643-8.

Tran, L., Basdevant, N., Prévost, C., Ha-Duong, T. Structure of Ring-Shaped Aβ42 Oligomers Determined by Conformational Selection. Scientific Reports, 6 (2016) 21429.

Tamano, H., Takeda, A. Age-Dependent Modification of Intracellular Zn2+ Buffering in the Hippocampus and Its Impact. Biol Pharm Bull, 42 (2019) 1070-5.

Arispe, N., Pollard, H.B., Rojas, E. Zn2+ interaction with Alzheimer amyloid beta protein calcium channels. Proc. Natl. Acad. Sci. U.S.A, 93 (1996) 1710-5.

Corona, C., Pensalfini, A., Frazzini, V., Sensi, S.L. New therapeutic targets in Alzheimer's disease: brain deregulation of calcium and zinc. Cell Death Dis, 2 (2011) e176-e.

Oostenbrink, C., Villa, A., Mark, A.E., Van Gunsteren, W.F. A Biomolecular Force Field Based on the Free Enthalpy of Hydration and Solvation: The GROMOS Force-Field Parameter Sets 53A5 and 53A6. J. Comput. Chem., 25 (2004) 1656-76.

Nagle, J.F. Area/Lipid of Bilayers from NMR. Biophys. J., 64 (1993) 1476-81.

Abraham, M.J., Murtola, T., Schulz, R., Páll, S., Smith, J.C., Hess, B., et al. GROMACS: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers. SoftwareX, 1–2 (2015) 19-25.

Ngo, S.T. Computational Investigations of the Transmembrane Italian-Mutant (E22K) 3Aβ11−40 in Aqueous Solution. Communications in Physics, 28 (2018) 265-76.

Darden, T., York, D., Pedersen, L. Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems. J. Chem. Phys., 98 (1993) 10089-92.

Ngo, S.T., Hung, H.M., Nguyen, M.T. Fast and Accurate Determination of the Relative Binding Affinities of Small Compounds to HIV-1 Protease using Non-Equilibrium Work. J. Comput. Chem., 37 (2016) 2734-42.

Ngo, S.T., Nguyen, M.T., Nguyen, M.T. Determination of the absolute binding free energies of HIV-1 protease inhibitors using non-equilibrium molecular dynamics simulations. Chem. Phys. Lett., 676 (2017) 12-7.

Torrie, G.M., Valleau, J.P. Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling. J. Comput. Phys., 23 (1977) 187-99.

Hub, J.S., de Groot, B.L., van der Spoel, D. g_wham—A Free Weighted Histogram Analysis Implementation Including Robust Error and Autocorrelation Estimates. J. Chem. Theory Comput., 6 (2010) 3713-20.

Efron, B. Bootstrap Methods: Another Kook at the Jackknife. Ann. Stat., 7 (1979) 1-26.

Petrache, H.I., Dodd, S.W., Brown, M.F. Area per Lipid and Acyl Length Distributions in Fluid Phosphatidylcholines Determined by (2)H NMR Spectroscopy. Biophys. J., 79 (2000) 3172-92.

Ngo, S.T., Nguyen, M.T., Nguyen, N.T., Vu, V.V. The Effects of A21G Mutation on Transmembrane Amyloid Beta (11–40) Trimer: an In Silico Study. J. Phys. Chem. B, 121 (2017) 8467-74.

Ngo, S.T., Hung, H.M., Tran, K.N., Nguyen, M.T. Replica Exchange Molecular Dynamics Study of the Amyloid Beta (11-40) Trimer Penetrating a Membrane. RSC Adv., 7 (2017) 7346-57.

Tieleman, D.P., Marrink, S.J., Berendsen, H.J.C. A Computer Perspective of Membranes: Molecular Dynamics Studies of Lipid Bilayer Systems. BBA-Rev. Biomembranes, 1331 (1997) 235-70.

Hung, H.M., Nguyen, V.P., Ngo, S.T., Nguyen, M.T. Theoretical Study of the Interactions between the first Transmembrane Segment of NS2 Protein and a POPC Lipid Bilayer. BioPhys Chem, 217 (2016) 1-7.

Di Scala, C., Yahi, N., Boutemeur, S., Flores, A., Rodriguez, L., Chahinian, H., et al. Common molecular mechanism of amyloid pore formation by Alzheimer’s β-amyloid peptide and α-synuclein. Sci Rep, 6 (2016) 28781.

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