Modeling Cu2+-Aβ complexes from computational approaches

Alí‐Torres, Jorge; Mirats, Andrea; Maréchal, Jean‐Didier; Rodrı́guez-Santiago, Luis; Sodupe, Mariona

doi:10.1063/1.4921072

Cited by 19 publications

(7 citation statements)

References 66 publications

(94 reference statements)

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“…BLYP is also tested here because it is the functional used in many previous CPMD/BOMD simulations of solvated copper ions (see below). MPWB1K, a meta-GGA functional, is tested because a recent study 52 found it to work well for several copper complexes. To obtain longer DFT/MM simulations, a small basis that contains the Hay−Wadt effective core potential (Lanl2dz 53 ) for copper and 6-31G(d) for other elements is used; gas phase calculations for copper−water complexes (Tables 1 and 2 and Supporting Information) indicate that this basis set leads to good geometries in comparison to calculations using aug-cc-pVTZ.…”

Section: Methodsmentioning

confidence: 99%

Copper Oxidation/Reduction in Water and Protein: Studies with DFTB3/MM and VALBOND Molecular Dynamics Simulations

et al. 2015

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We apply two recently developed computational methods, DFTB3 and VALBOND, to study copper oxidation/reduction processes in solution and protein. The properties of interest include the coordination structure of copper in different oxidation states in water or in a protein (plastocyanin) active site, the reduction potential of the copper ion in different environments, and the environmental response to copper oxidation. The DFTB3/MM and VALBOND simulation results are compared to DFT/MM simulations and experimental results whenever possible. For a solvated copper ion, DFTB3/MM results are generally close to B3LYP/MM with a medium basis, including both solvation structure and reduction potential for Cu(II); for Cu(I), however, DFTB3/MM finds a two-water coordination, similar to previous Born-Oppenheimer molecular dynamics simulations using BLYP and HSE, while B3LYP/MM leads to a tetrahedron coordination. For a tetra-ammonia copper complex in solution, VALBOND and DFTB3/MM are consistent in terms of both structural and dynamical properties of solvent near copper for both oxidation states. For copper reduction in plastocyanin, DFTB3/MM simulations capture the key properties of the active site, and the computed reduction potential and reorganization energy are in fair agreement with experiment, especially when periodic boundary condition is used. Overall, the study supports the value of VALBOND and DFTB3(/MM) to the analysis of fundamental copper redox chemistry in water and protein, and the results also help highlight areas where further improvements in these methods are desirable.

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Section: Methodsmentioning

confidence: 99%

Copper Oxidation/Reduction in Water and Protein: Studies with DFTB3/MM and VALBOND Molecular Dynamics Simulations

et al. 2015

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“…DFT and ab initio methods have been used to investigate copper-Aβ interactions, but their computational expense typically requires the use of model systems such as Cu–Aβ 1–16 or smaller. , In addition, hybrid quantum mechanics/molecular mechanics (QM/MM) was applied to Cu–Aβ 1–16 to model energetics and redox potentials of different Cu-binding modes. , QM/MM combined with homology modeling was carried out by Ali-Torres et al to probe the Cu(II)–Aβ 1–16 coordination sphere. The 3N1O model was considered with His6, His13 and His14 as nitrogen ligands, including δ and ε binding modes, with a range of potential residues for the oxygen ligand.…”

Section: Introductionmentioning

confidence: 99%

Metal Binding to Amyloid-β_1–42: A Ligand Field Molecular Dynamics Study

Mutter

Turner

Deeth

et al. 2018

ACS Chem. Neurosci.

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Ligand field molecular mechanics simulation has been used to model the interactions of copper(II) and platinum(II) with the amyloid-β peptide monomer. Molecular dynamics over several microseconds for both metalated systems are compared to analogous results for the free peptide. Significant differences in structural parameters are observed, both between Cu and Pt bound systems as well as between free and metal-bound peptide. Both metals stabilize the formation of helices in the peptide as well as reducing the content of β secondary structural elements compared to the unbound monomer. This is in agreement with experimental reports of metals reducing β-sheet structures, leading to formation of amorphous aggregates over amyloid fibrils. The shape and size of the peptide structures also undergo noteworthy change, with the free peptide exhibiting globular-like structure, platinum(II) system adopting extended structures, and copper(II) system resulting in a mixture of conformations similar to both of these. Salt bridge networks exhibit major differences: the Asp23-Lys28 salt bridge, known to be important in fibril formation, has a differing distance profile within all three systems studied. Salt bridges in the metal binding region of the peptide are strongly altered; in particular, the Arg5-Asp7 salt bridge, which has an occurrence of 71% in the free peptide, is reduced to zero in the presence of both metals.

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“…Structural details for naturally occurring metals such as Cu and Zn have been elucidated through a wide range of experimental [ 14 ][ 15 ] and simulation techniques,[ 16 ][ 17 ][ 18 ][ 19 ] but the equivalent for Pt is scarcer. Ma et al used HPLC, ESI-MS and NMR spectroscopy to examine the binding of Pt II -phenanthroline to Aβ, suggesting that binding to His6 and His14 predominates and that π-stacking to aromatic residues Phe4, Tyr10 and His13 may also play a role.…”

Section: Introductionmentioning

confidence: 99%

Ligand field molecular dynamics simulation of Pt(II)-phenanthroline binding to N-terminal fragment of amyloid-β peptide

et al. 2018

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We report microsecond timescale molecular dynamics simulation of the complex formed between Pt(II)-phenanthroline and the 16 N-terminal residues of the Aβ peptide that is implicated in the onset of Alzheimer’s disease, along with equivalent simulations of the metal-free peptide. Simulations from a variety of starting points reach equilibrium within 100 ns, as judged by root mean square deviation and radius of gyration. Platinum-bound peptides deviate rather more from starting points, and adopt structures with larger radius of gyration, than their metal-free counterparts. Residues bound directly to Pt show smaller fluctuation, but others actually move more in the Pt-bound peptide. Hydrogen bonding within the peptide is disrupted by binding of Pt, whereas the presence of salt-bridges are enhanced.

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Modeling Cu2+-Aβ complexes from computational approaches

Cited by 19 publications

References 66 publications

Copper Oxidation/Reduction in Water and Protein: Studies with DFTB3/MM and VALBOND Molecular Dynamics Simulations

Copper Oxidation/Reduction in Water and Protein: Studies with DFTB3/MM and VALBOND Molecular Dynamics Simulations

Metal Binding to Amyloid-β_1–42: A Ligand Field Molecular Dynamics Study

Ligand field molecular dynamics simulation of Pt(II)-phenanthroline binding to N-terminal fragment of amyloid-β peptide

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Modeling Cu2+-Aβ complexes from computational approaches

Cited by 19 publications

References 66 publications

Copper Oxidation/Reduction in Water and Protein: Studies with DFTB3/MM and VALBOND Molecular Dynamics Simulations

Copper Oxidation/Reduction in Water and Protein: Studies with DFTB3/MM and VALBOND Molecular Dynamics Simulations

Metal Binding to Amyloid-β1–42: A Ligand Field Molecular Dynamics Study

Ligand field molecular dynamics simulation of Pt(II)-phenanthroline binding to N-terminal fragment of amyloid-β peptide

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Metal Binding to Amyloid-β_1–42: A Ligand Field Molecular Dynamics Study