Revisiting Cu(II) Bound Amyloid-β40 and Amyloid-β42 Peptides: Varying Coordination Chemistries

Year 2018, Volume: 5 Issue: 3, 981 - 1008, 01.09.2018

Orkid Coskuner-weber

https://doi.org/10.18596/jotcsa.424144

Cited By: 6

Abstract

Metal ions and intrinsically disordered peptides amyloid-β40
and amyloid-β42 are at the center of Alzheimer´s disease pathology. Divalent
copper ion binds to amyloid-β40 and amyloid-β42 peptides with varying
coordination chemistries. Experiments face challenges in the measurements of
divalent copper ion bound monomeric amyloid-β40 and amyloid-β42 in an aqueous
solution medium because of fast conformational changes, rapid aggregation
processes and solvent effects. Theoretical studies complement experiments and
provide insights at the atomic and molecular levels with dynamics. However,
until recently, potential functions for simulating divalent copper ion bound
amyloid-β40 and amyloid-β42 peptides with varying coordination chemistries were
lacking. Using new potential functions that were developed for divalent copper
centers, Cu(II), including three histidine residues and an oxygen-ligated amino
acid residue, the structures and thermodynamic properties of Cu(II)-bound
amyloid-β40 and amyloid-β42 peptides in an aqueous solution medium were
studied. For these purposes, extensive first principles calculations and
replica exchange molecular dynamics simulations were conducted. In this study,
the secondary and tertiary structural properties, conformational Gibbs free
energy values, potential of mean force surfaces, salt bridges and aggregation
propensities of aqueous Cu(II)-bound amyloid-β40 and amyloid-β42 peptides are
presented. Different than previous findings in the literature, results clearly
show that the coordination chemistry variations impact the structural and
thermodynamic properties of divalent Cu(II) bound amyloid-β alloforms in water.
Specificities about these differences are revealed in this study at the atomic
level with dynamics. Results presented herein are the first to offer a
comparison of the monomeric Cu(II)-bound amyloid-β40 and amyloid-β42 peptides
with varying coordination chemistries using bonded model potential functions.

Keywords

Copper, amyloid-β, coordination chemistry, replica exchange molecular dynamics simulations, Alzheimer's disease

References

• 1. Faller P, Hureau C. Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-beta peptide. Dalton Trans. 2009 Feb;21:1080-1094.
• 2. Atwood C. S, Moir R. D, Huang X. D, Scarpa R. C, Bacarra N. M, Romano D. M, Hartshorn M. K, Tanzi R. E, Bush A. I. Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis. J. Biol. Chem. 1998 May;273:12817-12826.
• 3. Zou J, Kajita K, Sugimoto N. Cu2+ inhibits the aggregation of amyloid beta-peptide(1-42) in vitro. Angew. Chem. Int. Ed. 2001 Jun; 40:2274-2277.
• 4. Raman B, Ban T, Yamagucchi K, Sakai M. Kawai T, Naiki H, Goto Y. Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid beta peptide. J. Biol. Chem. 2005 Apr; 280:16157-16162.
• 5. House E, Collingwood J, Khan A, Korchazkina O, Berthon G, Exley C. Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of A beta(42) in a manner which may have consequences for metal chelation therapy in Alzheimer's disease. J. Alz. Dis. 2004 Jun;6:291-301.
• 6. Yang X-H, Huang H-C, Chen L, Xu W, Jiang Z-F. Coordinating to Three Histidine Residues: Cu (II) Promotes Oligomeric and Fibrillar Amyloid-β Peptide to Precipitate in a Non-β Aggregation Manner. J. Alz. Dis. 2009 Nov;18:799-810.
• 7. Yu H, Ren J, Qu X. Different Hydration Changes Accompanying Copper and Zinc Binding to Amyloid β-Peptide: Water Contribution to Metal Binding. ChemBioChem. 2008 Feb;9:879-882.
• 8. Dai X, Sun Y, Gao Z, Jiang Z. Copper enhances amyloid-β peptide neurotoxicity and non β-aggregation: a series of experiments conducted upon copper-bound and copper-free amyloid-β peptide. J. Mol. Neurosci. 2010 May;41:66-73.
• 9. Hou L, Zagorski M G. NMR reveals anomalous copper(II) binding to the amyloid A beta peptide of Alzheimer's disease. J. Am. Chem. Soc. 2006 Jun;128:9260-9261.
• 10. Yoshiike Y, Tanemura K, Murayama O, Akagi T, Murayama M, Sato S, Sun X Y, Tanaka N, Takashima A. New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity. J. Biol. Chem. 2001 Aug; 276:32293-32299.
• 11. Smith D. P, Ciccotosto G. D, Tew D. J, Fodero-Tavoletti M. T, Johanssen T, Masters C. L, Barnham K. J, Cappai R. Concentration dependent Cu2+ induced aggregation and dityrosine formation of the Alzheimer's disease Amyloid-β peptide Biochem. 2007 Mar;46:2881-2891.
• 12. Jun S, Saxena S. The aggregated state of amyloid-beta peptide in vitro depends on Cu2+ ion concentration. Angew. Chem. Int. Edit. 2007 May;46:3959-3961.
• 13. Bolognin S, Messori L, Drago D, Gabbiani C, Cendron L, Zatta P. Aluminum, copper, iron and zinc differentially alter amyloid-Aβ< sub> 1–42</sub> aggregation and toxicity. Int. J Biochem. & Cell Biol. 2011 Jun;43:877-885.
• 14. Mold M, Ouro-Gnao L, Wieckowski B. M, Exley C. Copper prevents amyloid-[bgr] 1-42 from forming amyloid fibrils under near-physiological conditions in vitro. Scientific Reports. 2013 Feb;3:1256.
• 15. Hane F, Tran G, Attwood S. J, Leonenko Z. Cu2+ affects amyloid-β (1–42) aggregation by increasing peptide-peptide binding forces. PloS one. 2013 Mar;8:e59005.
• 16. Attanasio F, De Bona P, Cataldo S, Sciacca M. F. M, Milardi D, Pignataro B, Pappalardo G. Copper(II) and zinc(II) dependent effects on A beta 42 aggregation: a CD, Th-T and SFM study. New J. Chem. 2013 37(4):1206-1215.
• 17. Huang X. D, Atwood C. S, Moir R. D, Hartshorn M. A, Tanzi R. E, Bush A. I. Trace metal contamination initiates the apparent auto-aggregation, amyloidosis, and oligomerization of Alzheimer's A beta peptides. J. Biol. Inorg. Chem. 2004 Dec;9:954-960.
• 18. Karr J. W, Szalai V. A. Role of aspartate-1 in Cu(II) binding to the amyloid-β peptide of Alzheimer's disease. J. Am. Chem. Soc. 2007 Mar;129:3796-3797.
• 19. Karr J. W, Kaupp L. J, Szalai V. A. Amyloid-beta binds Cu2+ in a mononuclear metal ion binding site. J. Am. Chem. Soc. 2004 Oct;126:13534-13538.
• 20. Sarell C. J, Wilkinson S. R, Viles J. H. Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-beta from Alzheimer Disease. J. Biol. Chem. 2010 Dec;285:41533-41540.
• 21. Jun S, Gillespie J. R, Shin B.-k, Saxena S. The Second Cu(II)-Binding Site in a Proton-Rich Environment Interferes with the Aggregation of Amylold-beta(1-40) into Amyloid Fibrils. Biochem. 2009 Oct;48:10724-10732.
• 22. Lv Z, Condron M. M, Teplow D. B, Lyubchenko Y. L. Nanoprobing of the Effect of Cu 2D Cations on Misfolding, Interaction and Aggregation of Amyloid Beta Peptide. Biophys. J. 2013 Jan;104:513A-514A.
• 23. Bush A. I. The metallobiology of Alzheimer's disease. Trends in Neurosciences. 2003 Apr;26:207-214.
• 24. Opazo C, Huang X. D, Cherny R. A, Moir R. D, Roher A. E, White A. R, Cappai R, Masters C. L, Tanzi R. E, Inestrosa N. C, Bush A. I. Metalloenzyme-like activity of Alzheimer's disease beta-amyloid - Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. J. Biol. Chem. 2002 Oct;277:40302-40308.
• 25. Cuajungco M. P, Faget K. Y. Zinc takes the center stage: its paradoxical role in Alzheimer's disease. Brain Res. Rev. 2003 Jan;41:44-56.
• 26. Huang X. D, Atwood C. S, Hartshorn M. A, Multhaup G, Goldstein L. E, Scarpa R. C, Cuajungco M. P, Gray D. N, Lim, J, Moir R. D, Tanzi R. E, Bush A. I. The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochem. 1999 May;38:7609-7616.
• 27. Sharma A. K, Pavlova S. T, Kim J, Kim J, Mirica L. M. The effect of Cu2+ and Zn2+ on the A beta(42) peptide aggregation and cellular toxicity. Metallomics. 2013 Nov;5:1529-1536.
• 28. Huang X. D, Cuajungco M. P, Atwood C. S, Hartshorn M. A, Tyndall J. D. A, Hanson G. R, Stokes K. C, Leopold M, Multhaup G, Goldstein L. E, Scarpa R. C, Saunders A. J, Lim J, Moir R. D, Glabe C, Bowden E. F, Masters C. L, Fairlie D. P, Tanzi R. E, Bush A. I. Cu(II) potentiation of Alzheimer A beta neurotoxicity - Correlation with cell-free hydrogen peroxide production and metal reduction. J. Biol. Chem. 1999 Dec;274:37111-37116.
• 29. Nadal R. C, Rigby S. E. J, Viles J. H. Amyloid beta-Cu2+ Complexes in both Monomeric and Fibrillar Forms Do Not Generate H2O2 Catalytically but Quench Hydroxyl Radicals. Biochem. 2008 Nov;47:11653-11664.
• 30. Fang C.-L, Wu W.-H, Liu Q, Sun X. Ma Y, Zhao Y.-F, Li Y.-M. Dual functions of beta-amyloid oligomer and fibril in Cu(II)-induced H2O2 production. Regulatory Peptides. 2010 May;163:1-6.
• 31. Garzon-Rodriguez W, Yatsimirsky A. K, Glabe C. G. Binding of Zn(II), Cu(II), and Fe(II) ions to Alzheimer's A beta peptide studied by fluorescence. Bioorganic & Medicinal Chemistry Letters. 1999 Aug;9:2243-2248.
• 32. Atwood C. S, Scarpa R. C, Huang X. D, Moir R. D, Jones W. D, Fairlie D. P, Tanzi R. E, Bush A. I. Characterization of copper interactions with Alzheimer amyloid beta peptides: Identification of an attomolar-affinity copper binding site on amyloid beta 1-42. J. Neurochem. 2008 Sep;75:1219-1233.
• 33. Guilloreau L, Damian L, Coppel Y, Mazarguil H, Winterhalter M, Faller P. Structural and thermodynamical properties of CuII amyloid-β 16/28 complexes associated with Alzheimer's disease. J. Biol. Inorg. Chem. 2006 Aug;11:1024-1038.
• 34. Jiang D, Men L, Wang J, Zhang Y, Chickenyen S, Wang Y, Zhou F. Redox reactions of copper complexes formed with different beta-amyloid peptides and their neuropathalogical relevance. Biochem. 2007 Jul;46:9270-9282.
• 35. Karr J. W, Szalai V. A. Cu(II) binding to monomeric, oligomeric, and fibrillar forms of the Alzheimer's disease amyloid-beta peptide. Biochem. 2008 Apr;47:5006-5016.
• 36. Syme C. D, Nadal R. C, Rigby S. E. J, Viles J. H. Copper binding to the amyloid-beta (A beta) peptide associated with Alzheimer's disease - Folding, coordination geometry, pH dependence, stoichiometry, and affinity of A beta-(1-28): Insights from a range of complementary spectroscopic techniques. J. Biol. Chem. 2004 Apr;279:18169-18177.
• 37. Danielsson J, Pierattelli R, Banci L, Graslund A. High-resolution NMR studies of the zinc-binding site of the Alzheimer's amyloid beta-peptide. Febs J. 2007 Nov;274:46-59.
• 38. Bush A. I, Pettingell W. H, Multhaup G, Paradis M. D, Vonsattel J. P, Gusella J. F, Beyreuther K, Masters C. L, Tanzi R. E. Rapid Induction of Alzheimer a-Beta Amyloid Formation by Zinc. Science. 1994 Sep;265:1464-1467.
• 39. Tougu V, Karafin A, Palumaa P. Binding of zinc(II) and copper(II) to the full-length Alzheimer's amyloid-beta peptide. J. Neurochem. 2008 Mar;104:1249-1259.
• 40. Hatcher L. Q, Hong L, Bush W. D, Carducci T, Simon J. D. Quantification of the binding constant of copper(II) to the amyloid-beta peptide. J. Phys. Chem. B. 2008 Jul;112:8160-8164.
• 41. Karr J. W, Akintoye H, Kaupp L. J, Szalai V. A. N-terminal deletions modify the Cu2+ binding site in amyloid-beta. Biochem. 2005 Mar;44:5478-5487.
• 42. Kowalik-Jankowska T, Ruta M, Wisniewska K, Lankiewicz L. Coordination abilities of the 1-16 and 1-28 fragments of beta-amyloid peptide towards copper(II) ions: a combined potentiometric and spectroscopic study. J. Inorg. Biochem. 2003 Jul;95:270-282.
• 43. Ma Q.-F, Hu J, Wu W.-H, Liu H.-D, Du J.-T, Fu Y, Wu Y.-W, Lei P, Zhao Y.-F, Li Y.-M. Characterization of copper binding to the peptide amyloid-beta(1-16) associated with Alzheimer's disease. Biopolymers. 2006 Apr;83:20-31.
• 44. Hong L, Bush W. D, Hatcher L. Q, Simon J. Determining thermodynamic parameters from isothermal calorimetric isotherms of the binding of macromolecules to metal cations originally chelated by a weak ligand. J. Phys. Chem. B. 2008 Nov;112:604-611.
• 45. Curtain C. C, Ali F, Volitakis I, Cherny R. A, Norton R. S, Beyreuther K, Barrow C. J, Masters C. L, Bush A. I, Barnham K. J. Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem. 2001 Jun;276:20466-20473.
• 46. Minicozzi V, Stellato F, Comai M, Dalla Serra M, Potrich C, Meyer-Klaucke W, Morante S. Identifying the minimal copper- and zinc-binding site sequence in amyloid-beta peptides. J. Biol. Chem. 2008 Apr;283:10784-10792.
• 47. Miura T, Suzuki K, Kohata N, Takeuchi H. Metal binding modes of Alzheimer's amyloid beta-peptide in insoluble aggregates and soluble complexes. Biochem. 2000 May;39:7024-7031.
• 48. Stellato F, Menestrina G, Dalla Serra M, Potrich C, Tomazzolli R, Meyer-Klaucke W, Morante S. Metal binding in amyloid β-peptides shows intra- and inter-peptide coordination modes. Eur. Biophys. J. 2006 Jan;35:340-351.
• 49. Ma Q. F, Hu J, Wu W. H, Liu H. D, Du J. T, Fu Y, Wu Y. W, Lei P, Zhao Y. F, Li Y. M. Characterization of copper binding to the peptide amyloid-beta(1-16) associated with Alzheimer's disease. Biopoly. 2006 Apr;83:20-31.
• 50. Streltsov V. A, Titmuss S. J, Epa V. C, Barnham K. J, Masters C. L, Varghese J. N. The structure of the amyloid-beta peptide high-affinity copper II binding site in Alzheimer disease. Biophys. J. 2008 Oct;95:3447-3456.
• 51. Drew S. C, Noble C. J, Masters C. L, Hanson G. R, Barnham K. J. Pleomorphic Copper Coordination by Alzheimer's Disease Amyloid-beta Peptide. J. Am. Chem. Soc. 2009 Jan;131:1195-1207.
• 52. Kowalik-Jankowska T, Ruta-Dolejsz M, Wisniewska K, Lankiewicz L. Cu(II) interaction with N-terminal fragments of human and mouse beta-amyloid peptide. J. Inorg. Biochem. 2001 Sep;86:535-545.
• 53. Curtain C. C, Ali F. E, Smith D. G, Bush A. I, Masters C. L, Barnham K. J. Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-beta peptide with membrane lipid. J. Biol. Chem. 2003 Jan;278:2977-2982.
• 54. Shin B.-k, Saxena S. Direct evidence that all three histidine residues coordinate to Cu(II) in amyloid-beta(1-16). Biochem. 2008 Sep;47:9117-9123.
• 55. Barnham K. J, Haeffner F, Ciccotosto G. D, Curtain C. C, Tew D, Mavros C, Beyreuther K, Carrington D, Masters C. L, Cherny R. A, Cappai R, Bush A. I. Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease beta-amyloid. Faseb J. 2004 Jul;18:1427-1428.
• 56. Liao Q, Kammerlin S. C. L, Strodel B. Development and application of a nonbonded Cu(II) model that includes Jahn-Teller effect. Phys. Chem. Lett. 2015 Jun; 6:2657-2662.
• 57. Liao Q, Owen M. C., Olubiyi O. O, Bogdan B, Strodel B. Conformational Transitions of the Amyloid-β Peptide Upon Cu(II) Binding and pH Changes. Isr. J. Chem. 2017; 57:1-15.
• 58. Liao Q, Owen M. C, Bali S, Barz B, Strodel B. Aβ under stress: the effects of acidosis, Cu(II) binding, and oxidation on amyloid-β peptide dimers. Chem Commun. 2018 Jun; 54:7766-7769.
• 59. Ando K. The axial methionine ligand may control the redox reorganizations in the active site of blue copper proteins. J. Chem. Phys. 2010 Nov;133:0175101.
• 60. Bruschi M, Bertini L, Bonacic-Koutecky V, De Gioia L, Mitric R, Zampella G, Fantucci P. Speciation of Copper-Peptide Complexes in Water Solution Using DFTB and DFT Approaches: Case of the Cu(HGGG)(Py) Complex. J. Phys. Chem. B. 2012 Jun;116:6250-6260.
• 61. Hewitt N, Rauk A. Mechanism of Hydrogen Peroxide Production by Copper-Bound Amyloid Beta Peptide: A Theoretical Study. J. Phys. Chem. B. 2009 Jan;113:1202-1209.
• 62. Hodak M, Chisnell R, Lu W, Bernholc J. Functional implications of multistage copper binding to the prion protein. Proc. Nat. Acad. Sci. USA 2009 Jul;106:11576-11581. DOI: 10.1073/pnas.0903807106.
• 63. Inoue T, Shiota Y, Yoshizawa K. Quantum Chemical Approach to the Mechanism for the Biological Conversion of Tyrosine to Dopaquinone. J. Am. Chem. Soc. 2008 Nov;130:16890-16897.
• 64. Kaila V. R. I, Johansson M. P, Sundholm D, Laakkonen L, Wikstrom M. The chemistry of the Cu-B site in cytochrome c oxidase and the importance of its unique His-Tyr bond. Biochim. Biophys. Acta-Bioenergetics. 2009 Apr;1787:221-233.
• 65. Konecny R, Li J, Fisher C. L, Dillet V, Bashford D, Noodleman L. CuZn superoxide dismutase geometry optimization, energetics, and redox potential calculations by density functional and electrostatic methods. Inorg. Chem. 1999 Feb;38:940-950.
• 66. Pavelka M, Simanek M, Sponer J, Burda J. V. Copper cation interactions with biologically essential types of ligands: A computational DFT study. J. Phys. Chem. A. 2006 Mar;110:4795-4809.
• 67. Prabhakar R, Siegbahn P. E. M. A theoretical study of the mechanism for the biogenesis of cofactor topaquinone in copper amine oxidases. J. Am. Chem. Soc. 2004 Mar;126:3996-4006.
• 68. Rickard G. A, Gomez-Balderas R, Brunelle P, Raffa D. F, Rauk A. Binding affinities for models of biologically available potential Cu(II) Ligands relevant to Alzheimer's disease: An ab initio study. J. Phys. Chem. A. 2005 Aug;109:8361-8370.
• 69. Rimola A, Rodriguez-Santiago, L, Sodupe M. Cation-pi interactions and oxidative effects on Cu+ and Cu2+ binding to Phe, Tyr, Trp, and his amino acids in the gas phase. Insights from first-principles calculations. J. Phys. Chem. B. 2006 Nov;110:24189-24199.
• 70. Rokhsana D, Dooley D. M, Szilagyi R. K. Structure of the oxidized active site of galactose oxidase from realistic in silico models. J. Am. Chem. Soc. 2006 Nov;128:15550-15551.
• 71. Rokhsana D, Howells A. E, Dooley D. M, Szilagyi R. K. Role of the Tyr-Cys Cross-link to the Active Site Properties of Galactose Oxidase. Inorg. Chem. 2012 Feb;51:3513-3524.
• 72. Sabolovic J, Tautermann C. S, Loerting T, Liedl K. R. Modeling anhydrous and aqua copper(II) amino acid complexes: A new molecular mechanics force field parametrization based on quantum chemical studies and experimental crystal data. Inorg. Chem. 2003 Mar;42:2268-2279.
• 73. Blomberg M. R. A, Siegbahn P. E. M. Quantum chemistry applied to the mechanisms of transition metal containing enzymes - Cytochrome c oxidase, a particularly challenging case. J. Comp. Chem. 2006 Jun;27:1373-1384.
• 74. Hong G, Ivnitski D. M, Johnson G. R, Atanassov P, Pachter R. Design Parameters for Tuning the Type 1 Cu Multicopper Oxidase Redox Potential: Insight from a Combination of First Principles and Empirical Molecular Dynamics Simulations. J. Am. Chem. Soc. 2011 Apr;133(13):4802-4809.
• 75. Moon S, Patchkovskii S, Salahub D. R. QM/MM calculations of EPR hyperfine coupling constants in blue copper proteins. J. Mol. Struct.-Theochem. 2003 Aug;632:287-295.
• 76. Rodriguez-Granillo A, Crespo A, Wittung-Stafshede P. Conformational Dynamics of Metal-Binding Domains in Wilson Disease Protein: Molecular Insights into Selective Copper Transfer. Biochem. 2009 Jun;48:5849-5863.
• 77. Rose F, Hodak M, Bernholc J. Mechanism of copper(II)-induced misfolding of Parkinson's disease protein. Scientific Reports. 2011 Jun;1:11.
• 78. Sinnecker S, Neese F. QM/MM calculations with DFT for taking into account protein effects on the EPR and optical spectra of metalloproteins. Plastocyanin as a case study. J. Comput. Chem. 2006 Jun;27:1463-1475.
• 79. Brancato G, Rega N, Barone V. Microsolvation of the Zn(II) ion in aqueous solution: A hybrid QM/MM MD approach using non-periodic boundary conditions. Chem. Phys. Lett. 2008 Dec;451:53-57.
• 80. Hartsough D. S. Merz K. M. Dynamic Force Field Models – Molecular-Dynamics Simulations of Human Carbonic-Anhydrase-II Using a Quantum-Mechnaical Molecular Mechanical Coupled Potential. J Phys Chem. 1995 Jul;99:11266-11275.
• 81. Ryde, U. The coordination of the catalytic zinc ion in alcohol dehydrogenase studied by combined quantum-chemical and molecular mechanics calculations. J. Computer-Aided Molecular Design. 1996 Jan;10(2):153-164.
• 82. Ryde U. Combined quantum and molecular mechanics calculations on metalloproteins" Current Opinion in Chemical Biology. 2003 Feb;7:136-142.
• 83. Mutter S. T, Deeth R. J, Turner M, Platts J. A. Benchmarking of copper(II) LFMM parameters for studying amyloid-β peptides. J. Biomol. Struct. Dyn. 2017 Apr;36:1145-1153.
• 84. Wise O, Coskuner O. New force field parameters for metalloproteins I: Divalent copper ion centers including three histidine residues and an oxygen‐ligated amino acid residue. J. Comput. Chem. 2014 Apr;35:1278-1289.
• 85. Coskuner O. Divalent copper ion bound amyloid-β(40) and amyloid-β(42) alloforms are less preferred than divalent zinc ion bound amyloid-β(40) and amyloid-β(42) alloforms. J. Biol. Inorg. Chem. 2016 Sept;21:957.
• 86. Coskuner Weber O, Uversky V. N. How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-β42 in water. Intrinsically Disordered Proteins. 2017 Oct;5:1.
• 87. Xu L, Wang X, Shan S, Wang X. Characterization of the polymorphic states of copper(II)‐bound Aβ(1–16) peptides by computational simulations. J. Comp. Chem. Aug;34:2524-2536.
• 88. Wise-Scira O, Xu L, Kitahara T, Perry G, Coskuner O. Amyloid-β peptide structure in aqueous solution varies with fragment size. J. Chem. Phys. 2011 Nov;135:205101.
• 89. Parthasarathy S, Long F, Miller Y, Xiao Y, McElheny D, Thurber K, Ma, Nussinov R, Ishii Y. Molecular-Level Examination of Cu2+ Binding Structure for Amyloid Fibrils of 40-Residue Alzheimer’s β by Solid-State NMR Spectroscopy. J. Am. Chem. Soc. 2011 Feb;133:3390-3400.
• 90. Domingo A, Angeli C, de Graaf C, Robert V. Electronic reorganization triggered by electron transfer: The intervalence charge transfer of a Fe3+/Fe2+ bimetallic complex. J. Comp. Chem. 2015 Mar;36:861-869.
• 91. Bixon M, Jortner J. Electron Transfer – from Isolated Molecules to Biomolecules. 1999. John Wiley & Sons. ISBN: 9780471252924.
• 92. Coskuner O, Bergeron D. E, Rincon L, Hudgens J. W, Gonzalez C. A. Identification of Active Sites of Biomolecules. 1. Methyl-α-mannopyranoside and FeIII. J. Phys. Chem. A 2008 Feb;112:2940-2947.
• 93. Coskuner O, Bergeron D. E, Rincon L, Hudgens J. W, Gonzalez C. A. Identification of active sites of biomolecules II: Saccharide and transition metal ion in aqueous solution. J. Phys. Chem. A 2009 Feb;113:2491-2499.
• 94. Kodali R, Williams A. D, Chemuru S, Wetzel R. Aβ(1–40) Forms Five Distinct Amyloid Structures whose β-Sheet Contents and Fibril Stabilities Are Correlated. J. Mol. Biol. 2010 Aug;401:503-517.
• 95. Tycko R, Wickner R. B. Molecular structures of amyloid and prion fibrils: consensus versus controversy. Acc. Chem. Res. 2013 Jul;46:1487-1496.
• 96. Wise-Scira O, Xu L, Perry G, Coskuner O. Structures and free energy landscapes of aqueous zinc(II)-bound amyloid-β(1–40) and zinc(II)-bound amyloid-β(1–42) with dynamics. J. Biol. Inorg. Chem. 2012 Jun;17:927-938.
• 97. Sharma A. K, Pavlova S. T, Kim J, Finkelstein D, Hawco N. J, Rath N. P, Kim J, Mirica L. M. Bifunctional compounds for controlling metal-mediated aggregation of the aβ42 peptide. J. Am. Chem. Soc. 2012 Apr;134:6625-6636.
• 98. Asandei A, Schiopu I, Iftemi S, Mereuta L, Luchian T. Investigation of Cu2+ binding to human and rat amyloid fragments Aβ (1-16) with a protein nanopore. Langmuir 2013 Dec;29:15634-15642.
• 99. Morante S. The Role of Metals in β -Amyloid Peptide Aggregation: X-Ray Spectroscopy and Numerical Simulations. Curr. Alz. Res. 2008 Dec;5:508-524.
• 100. Silva K. I, Michael B. C, Geib S. J, Saxena S. ESEEM Analysis of Multi-Histidine Cu(II)-Coordination in Model Complexes, Peptides, and Amyloid-β. J. Phys. Chem. B 2014 Jul;118:8935-8944.
• 101. El Khoury Y, Dorlet P, Faller P, Hellwig P. New Insights into the Coordination of Cu(II) by the Amyloid-B 16 Peptide from Fourier Transform IR Spectroscopy and Isotopic Labeling. J. Phys. Chem. B 2011 Oct;115:14812-14821.
• 102. Hane F, Tran G, Attwood S. J, Leonenko Z. Cu(2+) affects amyloid-β (1-42) aggregation by increasing peptide-peptide binding forces. PLoS One 2013 Mar;8:e59005.
• 103. Nair N. G, Perry G, Smith M. A, Reddy V. P. NMR studies of zinc, copper, and iron binding to histidine, the principal metal ion complexing site of amyloid-beta peptide. J. Alz. Dis. 2010 Mar;20:57-66.
• 104. Allison T. C, Coskuner O, Gonzalez C. A. Metallic Systems: A Quantum Chemist´s Perspective. Boca Raton CRC Press/Taylor & Francis; 2011432 p. ISBN: 978-4200-6986-7.
• 105. Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C. Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins. 2006 Nov;65:712-725.
• 106. Binder K, Horbach J, Kob W, Paul W, Varnik F. Molecular dynamics simulations. J. Phys.: Cond. Matter 2004 Jan;16:S429-S453.
• 107. Beeman D. Some multistep methods for use in molecular dynamics calculations. J. Comput. Phys. 1976 Feb;20:130-139.
• 108. Xu L, Wang X, Wang X. Characterization of the internal dynamics and conformational space of zinc-bound amyloid β peptides by replica-exchange molecular dynamics simulations. 2013 July;42:575-586.
• 109. Xu L, Wang X, Wang X. Effects of Zn2+ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp1 or Glu11? 2013 Aug;4:1458-1468.
• 110. Prakash M. K, Barducci A, Parrinello M. Replica Temperatures for Uniform Exchange and Efficient Roundtrip Times in Explicit Solvent Parallel Tempering Simulations. J. Chem. Theory Comput. 2011 Jun;7:2025-2027.
• 111. Lee M. R, Duan Y, Kollman P. A. Use of MM-PB/SA in estimating the free energies of proteins: application to native, intermediates, and unfolded villin headpiece. Proteins. 2000 Jun;39:309-316.
• 112. Kollman P. A, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case D. A, Cheatham T. E. Calculating Structures and Free Energies of Complex Molecules:  Combining Molecular Mechanics and Continuum Models. Acc. Chem. Res. 2000 Oct;33:889-897.
• 113. Kabsch W, Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983 Dec;22:2577-2637.
• 114. Pawar A. P, DuBay K. F, Zurdo J, Chiti F, Vendruscolo M, Dobson C. M. Prediction of "aggregation-prone" and "aggregation-susceptible" regions in proteins associated with neurodegenerative diseases. J. Mol. Biol. 2005 Jul;350:379-392.
• 115. Nagypal I, Gergely A, Farkas E. Thermodynamic Study of Parent and Mixed Complexes of Aspartic-acid, Glutamic-acid and Glycine with Copper(II). Journal of Inorganic & Nuclear Chemistry. 1974 ;36:699-706.
• 116. Gassmann E, Kuo J. E, Zare R. N. Electrokinetic Separation of Chiral Compounds. Science. 1985 Nov;230:813-814.
• 117. Gozel P, Gassmann E, Michelsen H, Zare R. N. Electrokinetic Resolution of Amino-Acid Enantiomers with Copper(II) Aspartame Support Electrolyte. Analytical Chemistry. 1987 Jan;59:44-49.
• 118. Rickard G. A, Gomez-Balderas R, Brunelle P, Raffa D. F, Rauk A. Binding affinities for models of biologically available potential Cu(II) Ligands relevant to Alzheimer's disease: An ab initio study. J. Phys. Chem. A. 2005 Sep;109:8361-8370.
• 119. Smith D. P, Smith D. G, Curtain C. C, Boas J. F, Pilbrow J. R, Ciccotosto G. D, Lau T. L, Tew D. J, Perez K, Wade J. D, Bush A. I, Drew S. C, Separovic F, Masters C. L, Cappai R, Barnham K. J. Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge. J. Biol. Chem. 2006 Jun;281:15145-15154.
• 120. Cherny R. A, Atwood C. S, Xilinas M. E, Gray D. N, Jones W. D, McLean C. A, Barnham K. J, Volitakis I, Fraser F. W, Kim Y, Huang X, Goldstein L. E, Moir R. D, Lim J. T, Beyreuther K, Zheng H, Tanzi R. E, Masters C. L, Bush A. I. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001 Mar;30:665-676.
• 121. Cuajungco M. P, Goldstein L. E, Nunomura A, Smith M. A, Lim J. T, Atwood C. S, Huang X, Farrag Y. W, Perry G, Bush A. I. Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J. Biol. Chem. 2000 Jun;275:19439-19442.
• 122. Faller P. Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer. CHEMBIOCHEM. 2009 Dec;10:2837-2845.
• 123. Rajendran R, Minqin R, Ynsa M. D, Casadesus G, Smith M. A, Perry G, Halliwell B, Watt F. A novel approach to the identification and quantitative elemental analysis of amyloid deposits--insights into the pathology of Alzheimer's disease. Bichem. Biophys. Res. Commun. 2009 Apr;382:91-95.
• 124. 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 Jun;158:47-52.
• 125. Talmard C, Guilloreau L, Coppel Y, Mazarguil H, Faller P. Amyloid-beta peptide forms monomeric complexes with Cu(II) and Zn(II) prior to aggregation. CHEMBIOCHEM. 2007 Jan;8:163-165.
• 126. Sitkiewicz E, Kłoniecki M, Poznański J, Bal W, Dadlez M. Factors influencing compact-extended structure equilibrium in oligomers of aβ1-40 peptide--an ion mobility mass spectrometry study. J. Mol. Biol. 2014 Jul;426:2871-2885.
• 127. Noy D. Solomonov I, Sinkevich O, Arad T, Kjaer K, Sagi I. Zinc-Amyloid β Interactions on a Millisecond Time-Scale Stabilize Non-fibrillar Alzheimer-Related Species. J. Am. Chem. Soc. 2008 Jan;130:1376-1383.
• 128. Yang M, Teplow D. B. Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences. J. Mol. Biol. 2008 Dec;384:450-464.
• 129. Walsh D. M, Lomakin A, Benedek G. B, Condron M. M, Teplow D. B. Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J. Biol. Chem. 1997 Aug;272:22364-22372.
• 130. Bitan G, Kirkitadze M. D, Lomakin A, Vollers S. S, Benedek G. B, Teplow D. B. Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc. Natl. Acad. Sci. USA 2003 Jan;100:330-335.
• 131. Raffa D. F, Rauk A. Molecular Dynamics Study of the Beta Amyloid Peptide of Alzheimer's Disease and Its Divalent Copper Complexes. J. Phys. Chem. B. 2007 Mar;111:3789-3799.
• 132. Boopathi S, Kolandaivel P. Role of zinc and copper metal ions in amyloid β-peptides Aβ1–40 and Aβ1–42 aggregation. RSC Adv. 2014 Aug;4:38951-38965.
• 133. Dong M, Li H, Hu D, Zhao W, Zhu W, Ai H. Molecular Dynamics Study on the Inhibition Mechanisms of Drugs CQ1–3 for Alzheimer Amyloid-β40 Aggregation Induced by Cu2+. ACS Chem. Neurosci. 2016 Feb;7:599-614.
• 134. Velez-Vega C, Escobedo F. A. Characterizing the Structural Behavior of Selected Aβ-42 Monomers with Different Solubilities. J. Phys. Chem. B. 2011 Apr;115:4900-4910.
• 135. Yang C, Li J, Li Y, Zhu X. The effect of solvents on the conformations of Amyloid β-peptide (1–42) studied by molecular dynamics simulation. J. Mol. Struct. (THEOCHEM) Jan;895:1-8.
• 136. Sgourakis N. G, Yan Y, McCallum S. A, Wang C, Garcia A. E. The Alzheimer's peptides Abeta40 and 42 adopt distinct conformations in water: a combined MD / NMR study. J. Mol. Biol. 2007 May;368:1448-1457. 137. Yan Y, Wang C. Abeta42 is more rigid than Abeta40 at the C terminus: implications for Abeta aggregation and toxicity. J. Mol. Biol. 2006 Dec;364:853-862.
• 138. Foloppe N, Hartmann B, Nilson L, MacKerell A. D. Intrinsic conformational energetics associated with the glycosyl torsion in DNA: a quantum mechanical study. Biophys. J. 2002 Mar;82:1554-1569.
• 139. Mantri Y, Fioroni M, Baik M-H. Computational study of the binding of CuII to Alzheimer's amyloid-beta peptide: do Abeta42 and Abeta40 bind copper in identical fashion? J. Biol. Inorg. Chem. 2008 Nov;13:1197-1204.