Role of zinc and copper metal ions in amyloid β-peptides Aβ<sub>1–40</sub>and Aβ<sub>1–42</sub>aggregation

Boopathi, Subramanian; Kolandaivel, P.

doi:10.1039/c4ra05390g

Cited by 38 publications

(59 citation statements)

References 58 publications

(97 reference statements)

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“…The Aβ 40 generates a monomer, dimer, trimer, and tetramer, whereas Aβ 42 forms pentamer, hexamer, dodecamers, octadecamers, and oligomers. Between these two pepides, Aβ 42 has exhibits greater aggregation propensity than Aβ 40 peptide . The Aβ 42 monomer is the basic building block to aggregation of dimer, trimer and oligomers, so the structural characterization of the monomer at atomic level is important to explain the aggregation mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Fe²⁺binding on amyloid β-peptide promotes aggregation

Boopathi

Kolandaivel

2016

Proteins

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The metal ions Zn(2+) , Cu(2+) , and Fe(2+) play a significant role in the aggregation mechanism of Aβ peptides. However, the nature of binding between metal and peptide has remained elusive; the detailed information on this from the experimental study is very difficult. Density functional theory (dft) (M06-2X/6-311++G (2df,2pd) +LANL2DZ) has employed to determine the force field resulting due to metal and histidine interaction. We performed 200 ns molecular dynamics (MD) simulation on Aβ1-42 -Zn(2+) , Aβ1-42 -Cu(2+) , and Aβ1-42 -Fe(2+) systems in explicit water with different combination of coordinating residues including the three Histidine residues in the N-terminal. The present investigation, the Aβ1-42 -Zn(2+) system possess three turn conformations separated by coil structure. Zn(2+) binding caused the loss of the helical structure of N-terminal residues which transformed into the S-shaped conformation. Zn(2+) has reduced the coil and increases the turn content of the peptide compared with experimental study. On the other hand, the Cu(2+) binds with peptide, β sheet formation is observed at the N-terminal residues of the peptide. Fe(2+) binding is to promote the formation of Glu22-Lys28 salt-bridge which stabilized the turn conformation in the Phe19-Gly25 residues, subsequently β sheets were observed at His13-Lys18 and Gly29-Gly37 residues. The turn conformation facilitates the β sheets are arranged in parallel by enhancing the hydrophobic contact between Gly25 and Met35, Lys16 and Met35, Leu17 and Leu34, Val18 and Leu34 residues. The Fe(2+) binding reduced the helix structure and increases the β sheet content in the peptide, which suggested, Fe(2+) promotes the oligomerization by enhancing the peptide-peptide interaction. Proteins 2016; 84:1257-1274. © 2016 Wiley Periodicals, Inc.

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Section: Introductionmentioning

confidence: 99%

“…For instance, Zn 2+ promotes rapid formation of non‐fibrillar aggregates, whereas Cu 2+ enhances the proportion of β‐sheet content in both Aβ 40 and Aβ 42 peptides. The increased proportion of β‐sheet for copper‐bound Aβ indicates the propensity of aggregation . The Fe 2+ is more concentrated in amyloid plaques .…”

Section: Introductionmentioning

confidence: 99%

Fe²⁺binding on amyloid β-peptide promotes aggregation

Boopathi

Kolandaivel

2016

Proteins

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“…The monomers are initially separated in the simulation cell, then aggregate to form stable dimers through salt-bridge and hydrophobic contacts. In our previous work, 31 it has been confirmed that the conformations of Ab 42 have interactions between the central hydrophobic core LVFFA (17)(18)(19)(20)(21) and hydrophobic c-terminus (Met35-Ala42) because of the distance of around 4-6.5 Å between the Ca(Val24)-Ca(Asn27) residues. In our previous work, 31 it has been confirmed that the conformations of Ab 42 have interactions between the central hydrophobic core LVFFA (17)(18)(19)(20)(21) and hydrophobic c-terminus (Met35-Ala42) because of the distance of around 4-6.5 Å between the Ca(Val24)-Ca(Asn27) residues.…”

Section: Deformation Energy Analysismentioning

confidence: 74%

“…The intermolecular saltbridge is formed between the residues Asp 23 and Lys 28 in the turn region of amino acids Ser26-Ile31. The average distance of the CO 2 À moiety of Asp 23 from the NH 3 À moiety of the Lys 28 residue in the intra-and inter-peptide salt-bridge 31 have been calculated and given in the Table 2 and Fig. 52 The salt-bridge formation between the Asp 23 and Lys 28 residues of the peptide is the driving force for joining the long networks of layered b sheets in the Ab peptides.…”

Section: Variation Of Salt-bridge (Asp 23 /Lys 28 ) Distancesmentioning

confidence: 99%

“…[55][56][57][58][59][60][61][62][65][66][67][68] Multicanonical-multioverlap molecular dynamics 62 has been performed to study the dimerization of the Ab 29-42 sequence, which showed the conformational changes from helical to strand structure by a step-by-step method. 31 Lemkul et al 15 have reported that if the morin molecule is bound with the bend region, the salt-bridge is destabilized. 52,53,69 These investigations provide information on the structure and stabilities of the dimers in the Ab fibrils.…”

Section: Variation Of Salt-bridge (Asp 23 /Lys 28 ) Distancesmentioning

confidence: 99%

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Study on the inter- and intra-peptide salt-bridge mechanism of Aβ_23–28oligomer interaction with small molecules: QM/MM method

Boopathi

Kolandaivel

2015

Mol. BioSyst.

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Amyloid β (Aβ) peptides have long been known to be a potential candidate for the onset of Alzheimer's disease (AD). The biophysical properties of Aβ42 peptide aggregates are of significant importance for the amyloid cascade mechanism of AD. It is necessary to design an inhibitor using small molecules to reduce the aggregation process in Aβ42 peptides. Attention has been given to use the natural products as anti-aggregation compounds, directly targeting Aβ peptides. Polyphenols have been extensively studied as a class of amyloid inhibitors. 9,10-Anthraquinone (AQ) is present in abundance in medicinal plants (rhubarb), the Trp-Pro-Tyr (TPT) peptide has been found in the venom of the black mamba snake, and the morin molecule is naturally present in wine and green tea; several other polyphenol derivatives are under clinical trials to develop anti-neurodegenerative drugs. In vitro and in vivo results strongly suggest that AQ and morin molecules are potential inhibitors of Aβ aggregation; however, the detailed understanding of the inhibition mechanism remains largely unknown. The formation of Aβ fibrils and oligomers requires a conformational change from α-helix to β-sheet, which occurs due to the formation of a salt-bridge between Asp(23) and Lys(28) residues. The present study focused on investigating the salt-bridge mechanism in the monomer, dimer and oligomer of the Aβ23-28 peptide during the interaction with TPT, morin and AQ molecules. Interaction energy and natural bond orbital analyses have been carried out using the ONIOM(M05-2X/6-31++G(d,p):UFF) method. The QM/MM studies have been performed to study the mechanism of salt-bridge formation during the inhibition process of amyloid β protein aggregation. The TPT molecule, which binds with the Asp(23) and Lys(28) residues of Aβ, prevents the salt-bridge formation between Asp(23) and Lys(28) residues and consequently the probability of the formation of Aβ fibrils is reduced.

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Rapid QM/MM approach for biomolecular systems under periodic boundary conditions: Combination of the density-functional tight-binding theory and particle mesh Ewald method

Nishizawa

Okumura

2016

J. Comput. Chem.

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A quantum mechanical/molecular mechanical (QM/MM) approach based on the density-functional tight-binding (DFTB) theory is a useful tool for analyzing chemical reaction systems in detail. In this study, an efficient QM/MM method is developed by the combination of the DFTB/MM and particle mesh Ewald (PME) methods. Because the Fock matrix, which is required in the DFTB calculation, is analytically obtained by the PME method, the Coulomb energy is accurately and rapidly computed. For assessing the performance of this method, DFTB/MM calculations and molecular dynamics simulation are conducted for a system consisting of two amyloid-β(1-16) peptides and a zinc ion in explicit water under periodic boundary conditions. As compared with that of the conventional Ewald summation method, the computational cost of the Coulomb energy by utilizing the present approach is drastically reduced, i.e., 166.5 times faster. Furthermore, the deviation of the electronic energy is less than 10-6 Eh. © 2016 Wiley Periodicals, Inc.

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Role of zinc and copper metal ions in amyloid β-peptides Aβ_1–40and Aβ_1–42aggregation

Abstract: Conformational structural changes of Aβ1–40 and Aβ1–42 monomers during the interaction of Cu2+ and Zn2+ metal ions.

Cited by 38 publications

References 58 publications

Fe²⁺binding on amyloid β-peptide promotes aggregation

Fe²⁺binding on amyloid β-peptide promotes aggregation

Study on the inter- and intra-peptide salt-bridge mechanism of Aβ_23–28oligomer interaction with small molecules: QM/MM method

Rapid QM/MM approach for biomolecular systems under periodic boundary conditions: Combination of the density-functional tight-binding theory and particle mesh Ewald method

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Role of zinc and copper metal ions in amyloid β-peptides Aβ1–40and Aβ1–42aggregation

Abstract: Conformational structural changes of Aβ1–40 and Aβ1–42 monomers during the interaction of Cu2+ and Zn2+ metal ions.

Cited by 38 publications

References 58 publications

Fe2+binding on amyloid β-peptide promotes aggregation

Fe2+binding on amyloid β-peptide promotes aggregation

Study on the inter- and intra-peptide salt-bridge mechanism of Aβ23–28oligomer interaction with small molecules: QM/MM method

Rapid QM/MM approach for biomolecular systems under periodic boundary conditions: Combination of the density-functional tight-binding theory and particle mesh Ewald method

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Product

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Role of zinc and copper metal ions in amyloid β-peptides Aβ_1–40and Aβ_1–42aggregation

Fe²⁺binding on amyloid β-peptide promotes aggregation

Fe²⁺binding on amyloid β-peptide promotes aggregation

Study on the inter- and intra-peptide salt-bridge mechanism of Aβ_23–28oligomer interaction with small molecules: QM/MM method