Effects of Zn2+ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp1 or Glu11?

Xu, Liang; Wang, Xiaojuan; Wang, Xicheng

doi:10.1021/cn4001445

Cited by 21 publications

(42 citation statements)

References 89 publications

(226 reference statements)

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“…The integration time step was 2 fs and exchange between replicas was attempted every 5 ps. Previous REMD simulations including our own suggest that the fluctuation of cumulative helix content throughout simulations is an excellent indicator to check the convergence of REMD simulations . As the cumulative helix percentage reaches to a plateau, we found that the system becomes equilibrium.…”

Section: Methodssupporting

confidence: 58%

“…Experimental observations reveal that Zn 2+ induces Aβ40/Aβ42 to form amorphous aggregates different from ordered fibril structure . Previous MD simulations also suggested that Zn 2+ ‐bound Aβ40/Aβ42 did not show higher propensity of β‐sheet . It is thus interesting to know if the binding of metal ions in the N terminus is independent of the conformational dynamics of the C terminus of Aβ42.…”

Section: Resultsmentioning

confidence: 99%

“…However, previous studies have shown that MM/GBSA method may not be suitable for the evaluation of free energies of disordered proteins . In particular, the NM method cannot discriminate the entropy difference between Aβ and its various mutations.…”

Section: Methodsmentioning

confidence: 99%

“…As a result, the propensity of β‐sheet formation in the C‐terminal domain markedly decreases. Although large‐scale MD simulations have been performed to investigate the effects of metal binding on the thermodynamics and kinetics of Aβ, the modulation effect of N‐terminal due to metal binding on the C‐terminal of Aβ have not been examined so far.…”

Section: Introductionmentioning

confidence: 99%

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Dual effects of familial Alzheimer's disease mutations (D7H, D7N, and H6R) on amyloid β peptide: Correlation dynamics and zinc binding

Chen

Wang

2014

Proteins

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Although the N-terminal region of Amyloid β (Aβ) peptides plays dual roles as metal-coordinating sites and conformational modulator, few studies have been performed to explore the effects of mutations at this region on the overall conformational ensemble of Aβ and the binding propensity of metal ions. In this work, we focus on how three familial Alzheimer's disease mutations (D7H, D7N, and H6R) alter the structural characteristics and thermodynamic stabilities of Aβ42 using molecular dynamics simulations. We observe that each mutation displays increased β-sheet structures in both N and C termini. In particular, both the N terminus and central hydrophobic region of D7H can form stable β-hairpin structures with its C terminus. The conserved turn structure at Val²⁴-Lys²⁸ in all peptides and Zn²⁺-bound Aβ42 is confirmed as the common structural motif to nucleate folding of Aβ. Each mutant can significantly increase the solvation free energy and thus enhance the aggregation of Aβ monomers. The correlation dynamics between Aβ(1-16) and Aβ(17-42) fragments are elucidated by linking the domain motions with the corresponding structured conformations. We characterize the different populations of correlated domain motions for each mutant from a more macroscopic perspective, and unexpectedly find that Zn²⁺-bound Aβ42 ensemble shares the same populations as Aβ42, indicating that the binding of Zn²⁺ to Aβ follows the conformational selection mechanism, and thus is independent of domain motions, even though the structures of Aβ have been modified at a residue level.

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Section: Methodssupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual effects of familial Alzheimer's disease mutations (D7H, D7N, and H6R) on amyloid β peptide: Correlation dynamics and zinc binding

Chen

Wang

2014

Proteins

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“…D22 or E23) of the salt-bridge with K28. (330) Due to the insolubility of Fe(III) even in the presence of Aβ no well-defined species for structural studies was so far obtained. (320,331) …”

Section: Interactions Of Aβ Peptides With Metal Ionsmentioning

confidence: 99%

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

et al. 2015

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Concentration Effect, Structural Properties, and Driving Force on Aβ₂₈ Dimerization with and without Zn²⁺ Cooperation: Learning from Replica Exchange Sampling**

et al. 2022

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Zn2+ is a very important factor in promoting the formation of amyloid beta (Aβ) aggregates and amyloid plaques. The Zn2+‐bound Aβ species generate amorphous or low molecular‐weight oligomers. However, it is a lack of studies to approach the starting structural features (dimerization) in Aβ nucleation processes with and without Zn2+, which is the key point in understanding Zn2+‐induced nucleation mechanisms. To better understand the effect of concentration, structural properties, and the driving force, 14 independent replica exchange molecular dynamics simulations were performed in Aβ28 dimerization with and without Zn2+ (zAβ28) cooperation. Our scanning results show that the aggregation propensity is easier in Aβ28‐Aβ28 and Aβ28‐zAβ28 systems than zAβ28‐zAβ28 system. In binding property, the Aβ28‐Aβ28 model (−61.5 kcal mol−1) is stronger than zAβ28‐zAβ28 (−26.6 kcal mol−1) and Aβ28‐zAβ28 (−7.24 kcal mol−1) models. Further analysis confirmed that H13 and H14 residues play specific roles in the three systems. The key point is the orientation of N atom of the imidazole ring in histidine residues. Furthermore, we discovered different driving forces for each system. Our current study contributes to the understanding of how the Aβ28 dimer interacts with Zn2+, which could lead to new insights into Zn2+‐induced nucleation mechanisms.

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Effects of Zn²⁺ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp¹ or Glu¹¹?

Abstract: . However, such preference is dependent on the relative populations of different conformations with specific Zn 2+ binding modes, and therefore could be shifted when experimental or simulation conditions are altered.

Cited by 21 publications

References 89 publications

Dual effects of familial Alzheimer's disease mutations (D7H, D7N, and H6R) on amyloid β peptide: Correlation dynamics and zinc binding

Dual effects of familial Alzheimer's disease mutations (D7H, D7N, and H6R) on amyloid β peptide: Correlation dynamics and zinc binding

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

Concentration Effect, Structural Properties, and Driving Force on Aβ₂₈ Dimerization with and without Zn²⁺ Cooperation: Learning from Replica Exchange Sampling**

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Effects of Zn2+ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp1 or Glu11?

Abstract: . However, such preference is dependent on the relative populations of different conformations with specific Zn 2+ binding modes, and therefore could be shifted when experimental or simulation conditions are altered.

Cited by 21 publications

References 89 publications

Dual effects of familial Alzheimer's disease mutations (D7H, D7N, and H6R) on amyloid β peptide: Correlation dynamics and zinc binding

Dual effects of familial Alzheimer's disease mutations (D7H, D7N, and H6R) on amyloid β peptide: Correlation dynamics and zinc binding

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

Concentration Effect, Structural Properties, and Driving Force on Aβ28 Dimerization with and without Zn2+ Cooperation: Learning from Replica Exchange Sampling**

Contact Info

Product

Resources

About

Effects of Zn²⁺ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp¹ or Glu¹¹?

Concentration Effect, Structural Properties, and Driving Force on Aβ₂₈ Dimerization with and without Zn²⁺ Cooperation: Learning from Replica Exchange Sampling**