Molecular Dynamics Simulation and Computational Two-Dimensional Infrared Spectroscopic Study of Model Amyloid β-Peptide Oligomers

Xu, Jun; Zhang, John Z. H.; Xiang, Yun

doi:10.1021/jp403748z

Cited by 9 publications

(13 citation statements)

References 69 publications

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“…This is in agreement with previous results. 11,12,43,44 After Zn 2+ coordination, it is clear that only one basin occurs in Zn 2+ -Aβ40 ( Figure 2B) and Zn 2+ -Aβ42 ( Figure 2D). The basin of Zn 2+ -Aβ40 (Zn 2+ -Aβ42) is located at R g value of 9.88−9.95 Å (9.90−10.10 Å) and RMSD value of 1.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Zn²⁺ Effect on Structure and Residual Hydrophobicity of Amyloid β-Peptide Monomers

2014

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The aggregation of amyloid β-peptide (Aβ peptide) has been associated with the pathogenesis of Alzheimer's disease (AD). In the present study, we aimed to disclose how Zn(2+) affects the Aβ aggregation in detail. Thus, molecular dynamics simulation was implemented to elucidate the changes of structure and residual hydrophobicity upon Zn(2+) coordination. Our results show that Zn(2+) can strongly influence the structural properties of Aβ40 and Aβ42 by reducing helical formation and increasing turn formation to expose the hydrophobic regions. Furthermore, hydrophobicity of Zn(2+)-Aβ40 and Zn(2+)-Aβ42 was much higher than that of each monomer, since Zn(2+) binding can significantly influence the hydrophilic domains of Aβ. The further analyses indicate that not only four residues (H6, E11, H13, and H14) but also R5, D7, K16, K28, and terminal residues influence hydrophobicity upon Zn(2+) coordination. Importantly, R5, K16, and K28 play a crucial role to regulate solvation-free energies. This work is helpful to understand the fundamental role of Zn(2+) in aggregation, which could be useful for further development of new drugs to inhibit Zn(2+)-Aβ aggregation.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Zn²⁺ Effect on Structure and Residual Hydrophobicity of Amyloid β-Peptide Monomers

2014

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“…Unlike previous studies, Xu et al started from fibril structures to generate oligomers but reached similar conclusions about the fact that monomeric Ab 1-40 is basically a random coil while oligomers are more fibril-like. 30 P. Derreumaux has extensively modeled and characterized the Ab aggregation of short peptides using REMD and found that oligomers adopt mainly mixed parallel-antiparallel b-strands but with predominance of antiparallel b-strands. 31,32 Employing a different methodology, Baftizadeh et al characterized the nucleation pathway from disordered aggregates of 18 polyvaline chains to ordered amyloid-like b-structures, reaching the important conclusion that the system first forms a relatively large ordered nucleus of antiparallel b-sheets before a few parallel sheets start appearing.…”

Section: Introductionmentioning

confidence: 99%

Energetic contributions of residues to the formation of early amyloid-β oligomers

Pouplana

Campanera

2015

Phys. Chem. Chem. Phys.

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Low-weight amyloid-β (Aβ) oligomers formed at early stages of oligomerization rather than fibril assemblies seem to be the toxic components that drive neurodegeneration in Alzheimer's disease. Unfortunately, detailed knowledge of the structure of these early oligomers at the residue level is not yet available. In this study, we performed all-atom explicit solvent molecular dynamics simulations to examine the oligomerization process of Aβ10-35 monomers when forming dimers, trimers, tetramers and octamers, with four independent simulations of a total simulated time of 3 μs for each oligomer system. The decomposition of the stability free energy by MM-GBSA methodology allowed us to unravel the network of energetic interactions that stabilize such oligomers. The contribution of the intermonomeric van der Waals term is the most significant energy feature of the oligomerization process, consistent with the so-called hydrophobic effect. Furthermore, the decomposition of the stability free energy into residues and residue-pairwise terms revealed that it is mainly apolar interactions between the three specific hydrophobic fragments 31-35 (C-terminal region), 17-20 (central hydrophobic core) and 12-14 (N-terminal region) that are responsible for such a favourable effect. The conformation in which the hydrophobic cthr-chc interaction is oriented perpendicularly is particularly important. We propose three other model substructures that favour the oligomerization process and can thus be considered as molecular targets for future inhibitors. Understanding Aβ oligomerization at the residue level could lead to more efficient design of inhibitors of this process.

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“…This process, considered to be a fundamental contributor to fibrillization and plaque formation, is initiated when Aβ transitions from α-helix to β-sheet secondary structure. This event precedes the pathological sequence of self-association, oligomerization and fibril formation, an end point that constitutes the structural basis of Aβ plaque deposits [5-7]. In addition, once produced, β-sheet conformers are capable of catalyzing the α-helix → β-sheet transition of other Aβ monomers [8, 9].…”

Section: Alzheimer’s Disease: Introduction and Overviewmentioning

confidence: 99%

Impact of Apolipoprotein E on Alzheimer’s Disease

Hauser¹,

Ryan²

2013

CAR

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A key feature of Alzheimer’s disease (AD) is deposition of extracellular amyloid plaque comprised chiefly of the amyloid β (Aβ) peptide. Studies of Aβ have shown that it may be catabolized by proteolysis or cleared from brain via members of the low-density lipoprotein receptor family. Alternatively, Aβ can undergo a conformational transition from α-helix to β-sheet, a conformer that displays a propensity to self-associate, oligomerize and form fibrils. Furthermore, β-sheet conformers catalyze conversion of other α-helical Aβ peptides to β-sheet, feeding the oligomer and fibril assembly process. A factor that influences the fate of Aβ in the extracellular space is apolipoprotein (apo) E. Polymorphism at position 112 or 158 in apoE give rise to three major isoforms. One isoform in particular, apoE4 (Arg at 112 and 158), has generated considerable interest since the discovery that it is the major genetic risk factor for development of late onset AD. Despite this striking correlation, the molecular mechanism underlying apoE4’s association with AD remains unclear. A tertiary structural feature distinguishing apoE4 from apoE2 and apoE3, termed domain interaction, is postulated to affect the conformation and orientation of its’ two independently folded domains. This feature has the potential to influence apoE4’s interaction with Aβ, its sensitivity to proteolysis or its lipid accrual and receptor binding activities. Thus, domain interaction may constitute the principal molecular feature of apoE4 that predisposes carriers to late onset AD. By understanding the contribution of apoE4 to AD at the molecular level new therapeutic or prevention strategies will emerge.

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Molecular Dynamics Simulation and Computational Two-Dimensional Infrared Spectroscopic Study of Model Amyloid β-Peptide Oligomers

Cited by 9 publications

References 69 publications

Zn²⁺ Effect on Structure and Residual Hydrophobicity of Amyloid β-Peptide Monomers

Zn²⁺ Effect on Structure and Residual Hydrophobicity of Amyloid β-Peptide Monomers

Energetic contributions of residues to the formation of early amyloid-β oligomers

Impact of Apolipoprotein E on Alzheimer’s Disease

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Molecular Dynamics Simulation and Computational Two-Dimensional Infrared Spectroscopic Study of Model Amyloid β-Peptide Oligomers

Cited by 9 publications

References 69 publications

Zn2+ Effect on Structure and Residual Hydrophobicity of Amyloid β-Peptide Monomers

Zn2+ Effect on Structure and Residual Hydrophobicity of Amyloid β-Peptide Monomers

Energetic contributions of residues to the formation of early amyloid-β oligomers

Impact of Apolipoprotein E on Alzheimer’s Disease

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Product

Resources

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Zn²⁺ Effect on Structure and Residual Hydrophobicity of Amyloid β-Peptide Monomers

Zn²⁺ Effect on Structure and Residual Hydrophobicity of Amyloid β-Peptide Monomers