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Development and Application of a Nonbonded Cu(2+) Model That Includes the Jahn-Teller Effect.

Liao Q, Kamerlin SC, Strodel B - J Phys Chem Lett (2015)

Bottom Line: This challenge is addressed in the current study, where, for the first time, a dummy model including a Jahn-Teller effect is developed for Cu(2+).We successfully validate its usefulness by studying metal binding in two biological systems: the amyloid-β peptide and the mixed-metal enzyme superoxide dismutase.We believe that our parameters will be of significant value for the computational study of Cu(2+)-dependent biological systems using classical models.

View Article: PubMed Central - PubMed

ABSTRACT
Metal ions are both ubiquitous to and crucial in biology. In classical simulations, they are typically described as simple van der Waals spheres, making it difficult to provide reliable force field descriptions for them. An alternative is given by nonbonded dummy models, in which the central metal atom is surrounded by dummy particles that each carry a partial charge. While such dummy models already exist for other metal ions, none is available yet for Cu(2+) because of the challenge to reproduce the Jahn-Teller distortion. This challenge is addressed in the current study, where, for the first time, a dummy model including a Jahn-Teller effect is developed for Cu(2+). We successfully validate its usefulness by studying metal binding in two biological systems: the amyloid-β peptide and the mixed-metal enzyme superoxide dismutase. We believe that our parameters will be of significant value for the computational study of Cu(2+)-dependent biological systems using classical models.

No MeSH data available.


Related in: MedlinePlus

Jahn–Teller effect and ΔGhyd for CuDum in water. (a) Radial distributionfunction (red, left y axis) and coordination number(blue, right y axis) for water around CuDum. Thefree energy contributions dGLJ/dλ(b) and dGelec/dλ (c) as a functionof the coupling parameter λ. ΔGLJ and ΔGelec are calculated by summing overthe 21 intermediate states ranging from λ = 0 to λ = 1applying eq S7. The standard deviationfor each state is shown by a blue bar (for some cases, it is <0.001kcal/mol and thus not visible) while the interpolation between thestates is shown in red. The experimental values are dCu–Oeq = 1.96 Å, dCu–Oax = 2.28 Å, and ΔGhyd = −496.16 kcal/mol.
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fig3: Jahn–Teller effect and ΔGhyd for CuDum in water. (a) Radial distributionfunction (red, left y axis) and coordination number(blue, right y axis) for water around CuDum. Thefree energy contributions dGLJ/dλ(b) and dGelec/dλ (c) as a functionof the coupling parameter λ. ΔGLJ and ΔGelec are calculated by summing overthe 21 intermediate states ranging from λ = 0 to λ = 1applying eq S7. The standard deviationfor each state is shown by a blue bar (for some cases, it is <0.001kcal/mol and thus not visible) while the interpolation between thestates is shown in red. The experimental values are dCu–Oeq = 1.96 Å, dCu–Oax = 2.28 Å, and ΔGhyd = −496.16 kcal/mol.

Mentions: The results for ZnDum were then taken for the developmentof CuDum.As Zn–O calculated with σZnO = 2.088 Åis quite close to the weighted mean distance between Cu2+ and oxygen (Cu–O, 2.07 Å), this σ together withthe other ZnDum parameters were used as a starting point and systematicallyoptimized for CuDum. In order to capture both the Jahn–Tellereffect (i.e., different Cu–O distances for equatorial and axialligands) and ΔGhyd, we tested different charge and distance distributions for the dummyatoms (Figures S3 and S4). We found thatreducing the charges for the axial and increasing them for the equatorialdummy atoms (based on q = 0.5e for the dummy atomsin ZnDum) is important for reproducing the Jahn–Teller effect(Figure S4). This reflects the fact thatequatorial interactions are preferred over axial coordination forCu2+ (d9) in aqueous solution. In combinationwith this charge disparity, a compressed octahedron performs betterthan elongated and regular octahedra. Despite the shorter distancesbetween Cu2+ and the axial dummy atoms, due to the largercharges of the equatorial dummy atoms, the resulting Cu–O distancesare shorter for the equatorial and not the axial ligands, in agreementwith the Jahn–Teller distortion in water. The compressed octahedroncombined with axial charges qax = 0.05eand equatorial charges qeq = 0.725e (Table 1) was identified as being able to reproduce boththe Jahn–Teller effect and ΔGhyd. The calculated Cu–O distances (dCu–Oeq = 1.94 Å and dCu–Oax = 2.26 Å) agreealmost perfectly with the corresponding experimental values of 1.96and 2.28 Å,29 and also the calculated ΔGhyd = −496.1kcal/mol deviates by less than 0.1 kcal/mol from the experimentalfinding (−496.16 kcal/mol)30 (Figure 3). It should be noted, though, that the metal solvationfree energies can largely deviate in different experimental studies.Following our earlier work,13 we use thedata presented by Noyes,30 which includesthermodynamic parameters for a wide range of metal centers, thus capturingthe relative effect of the different metals (for further discussionof this choice, see ref (13)). This Cu2+ dummy model was further validatedusing MD simulations of metalloproteins, which are discussed below.The usage of six dummy atoms generally favors hexacoordinated complexes.However, since the current model is a nonbonded model, it has theflexibility to adopt other geometries, such as five- or four-coordinatedgeometries where relevant. In the latter case, square-planar geometriesare favored due to the higher charges on the equatorial dummy atoms,which make them more attractive toward ligands than the axial dummyatoms. An alternative Cu2+ dummy model with larger chargeson the axial dummy atoms is presented in the SI. As can be seen from the results (Figures S5and S6) and the associated discussion, this model is also ableto produce good results in the MD simulations. Yet, CuDum better reproducesthe Jahn–Teller effect and ΔGhyd for Cu2+ in water and is thereforeour preferred model.


Development and Application of a Nonbonded Cu(2+) Model That Includes the Jahn-Teller Effect.

Liao Q, Kamerlin SC, Strodel B - J Phys Chem Lett (2015)

Jahn–Teller effect and ΔGhyd for CuDum in water. (a) Radial distributionfunction (red, left y axis) and coordination number(blue, right y axis) for water around CuDum. Thefree energy contributions dGLJ/dλ(b) and dGelec/dλ (c) as a functionof the coupling parameter λ. ΔGLJ and ΔGelec are calculated by summing overthe 21 intermediate states ranging from λ = 0 to λ = 1applying eq S7. The standard deviationfor each state is shown by a blue bar (for some cases, it is <0.001kcal/mol and thus not visible) while the interpolation between thestates is shown in red. The experimental values are dCu–Oeq = 1.96 Å, dCu–Oax = 2.28 Å, and ΔGhyd = −496.16 kcal/mol.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4493862&req=5

fig3: Jahn–Teller effect and ΔGhyd for CuDum in water. (a) Radial distributionfunction (red, left y axis) and coordination number(blue, right y axis) for water around CuDum. Thefree energy contributions dGLJ/dλ(b) and dGelec/dλ (c) as a functionof the coupling parameter λ. ΔGLJ and ΔGelec are calculated by summing overthe 21 intermediate states ranging from λ = 0 to λ = 1applying eq S7. The standard deviationfor each state is shown by a blue bar (for some cases, it is <0.001kcal/mol and thus not visible) while the interpolation between thestates is shown in red. The experimental values are dCu–Oeq = 1.96 Å, dCu–Oax = 2.28 Å, and ΔGhyd = −496.16 kcal/mol.
Mentions: The results for ZnDum were then taken for the developmentof CuDum.As Zn–O calculated with σZnO = 2.088 Åis quite close to the weighted mean distance between Cu2+ and oxygen (Cu–O, 2.07 Å), this σ together withthe other ZnDum parameters were used as a starting point and systematicallyoptimized for CuDum. In order to capture both the Jahn–Tellereffect (i.e., different Cu–O distances for equatorial and axialligands) and ΔGhyd, we tested different charge and distance distributions for the dummyatoms (Figures S3 and S4). We found thatreducing the charges for the axial and increasing them for the equatorialdummy atoms (based on q = 0.5e for the dummy atomsin ZnDum) is important for reproducing the Jahn–Teller effect(Figure S4). This reflects the fact thatequatorial interactions are preferred over axial coordination forCu2+ (d9) in aqueous solution. In combinationwith this charge disparity, a compressed octahedron performs betterthan elongated and regular octahedra. Despite the shorter distancesbetween Cu2+ and the axial dummy atoms, due to the largercharges of the equatorial dummy atoms, the resulting Cu–O distancesare shorter for the equatorial and not the axial ligands, in agreementwith the Jahn–Teller distortion in water. The compressed octahedroncombined with axial charges qax = 0.05eand equatorial charges qeq = 0.725e (Table 1) was identified as being able to reproduce boththe Jahn–Teller effect and ΔGhyd. The calculated Cu–O distances (dCu–Oeq = 1.94 Å and dCu–Oax = 2.26 Å) agreealmost perfectly with the corresponding experimental values of 1.96and 2.28 Å,29 and also the calculated ΔGhyd = −496.1kcal/mol deviates by less than 0.1 kcal/mol from the experimentalfinding (−496.16 kcal/mol)30 (Figure 3). It should be noted, though, that the metal solvationfree energies can largely deviate in different experimental studies.Following our earlier work,13 we use thedata presented by Noyes,30 which includesthermodynamic parameters for a wide range of metal centers, thus capturingthe relative effect of the different metals (for further discussionof this choice, see ref (13)). This Cu2+ dummy model was further validatedusing MD simulations of metalloproteins, which are discussed below.The usage of six dummy atoms generally favors hexacoordinated complexes.However, since the current model is a nonbonded model, it has theflexibility to adopt other geometries, such as five- or four-coordinatedgeometries where relevant. In the latter case, square-planar geometriesare favored due to the higher charges on the equatorial dummy atoms,which make them more attractive toward ligands than the axial dummyatoms. An alternative Cu2+ dummy model with larger chargeson the axial dummy atoms is presented in the SI. As can be seen from the results (Figures S5and S6) and the associated discussion, this model is also ableto produce good results in the MD simulations. Yet, CuDum better reproducesthe Jahn–Teller effect and ΔGhyd for Cu2+ in water and is thereforeour preferred model.

Bottom Line: This challenge is addressed in the current study, where, for the first time, a dummy model including a Jahn-Teller effect is developed for Cu(2+).We successfully validate its usefulness by studying metal binding in two biological systems: the amyloid-β peptide and the mixed-metal enzyme superoxide dismutase.We believe that our parameters will be of significant value for the computational study of Cu(2+)-dependent biological systems using classical models.

View Article: PubMed Central - PubMed

ABSTRACT
Metal ions are both ubiquitous to and crucial in biology. In classical simulations, they are typically described as simple van der Waals spheres, making it difficult to provide reliable force field descriptions for them. An alternative is given by nonbonded dummy models, in which the central metal atom is surrounded by dummy particles that each carry a partial charge. While such dummy models already exist for other metal ions, none is available yet for Cu(2+) because of the challenge to reproduce the Jahn-Teller distortion. This challenge is addressed in the current study, where, for the first time, a dummy model including a Jahn-Teller effect is developed for Cu(2+). We successfully validate its usefulness by studying metal binding in two biological systems: the amyloid-β peptide and the mixed-metal enzyme superoxide dismutase. We believe that our parameters will be of significant value for the computational study of Cu(2+)-dependent biological systems using classical models.

No MeSH data available.


Related in: MedlinePlus