Exploring the Alzheimer amyloid-β peptide conformational ensemble: A review of molecular dynamics approaches

Tran, Linh; Ha-Duong, Tâp

doi:10.1016/j.peptides.2015.04.009

Cited by 72 publications

(51 citation statements)

References 63 publications

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“…Most importantly,t he present secondary structure for the salt-containing pH 7.5 system almostr eproduces the NMR spectroscopicf indings of Hou et al [32] that Ab 42 peptides have residual b-strand structurei n two hydrophobic regions (Leu17-Ala21 and Ile31-Val36) and turn or bendlike structures in two largely hydrophilic regions (Asp7-Glu11a nd Phe20-Ser26). As reviewed by Tran and Ha-Duong, [33] the detailed folded structure of Ab 42 monomer is not unique and the question of the transients tructures of Ab 42 monomer in aqueous environmentr emains open, since different groups reported variousr esults for Ab 42 secondary structures. Still, our predictiono ft he secondary structure of Ab 42 is completely in line with the characteristics of the "converging model"o fT ran and Ha-Duong, [33] in which the unstructured N-terminal region( residues 1-10), the central b-rich hydrophobic core (residues 17-21),a nd b-strand-dominated C-terminus (residues 30-42), as well as consensually observed turn motifs (residues [22][23][24][25][26][27][28][29], are identified.…”

Section: Pk Andsalt Effects On Neutral Ab 42 Monomermentioning

confidence: 99%

Effect of pH on Aβ₄₂ Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

Zhao

2018

ChemPhysChem

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Amyloid beta-peptide (Aβ) is the key to developing Alzheimer's disease. Experiments have confirmed that different acidity influences directly not only the structural morphology and population of Aβ oligomers, but also the toxicity. The atomic-level association between the pH, charged residues, and Aβ properties remains obscure. Herein, conformational changes of Aβ monomer, fibril-like trimer, and pentamer in the medium pH range of 4.0-7.5 are studied. The results reveal that, as the pH changes from 7.5 to the isoelectric pH, His6, His13, and His14 are protonated in turn, successively approach the center of mass of folded Aβ monomer, trigger ionic interactions and changes of neighboring turns (Asp7-Ser8, His14-Lys16) and even a distant one (Leu34-Met35), as well as concomitant changes of secondary structure, and promote the conformation transition from unfolded to folded. This observation discloses that protonation can convert these charged residues from originally hydrophilic to "hydrophobic-like". For fibril-like oligomers, the pH susceptibility essentially stems from the pK values of charged residues in the context of the Aβ fibril, and in turn one can predict the dynamic behavior of these residues in the processes of dissociation or stabilization of a fibril by comparing the pK values of residues involved in salt bridges in the normal state with those in the current context. This idea is justified by two fibril models and appears to be applicable to other peptides and their fibril systems.

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Section: Pk Andsalt Effects On Neutral Ab 42 Monomermentioning

confidence: 99%

Effect of pH on Aβ₄₂ Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

Zhao

2018

ChemPhysChem

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“…The discrepancy in helix (S‐1, 800–1000 ns vs S‐2, 210–250 ns) for the S‐1 and S‐2 goes down (0.06 vs 0.0) from (0.14 (450–500 ns) vs 0.0 (210‐250 ns)), whereas that in turn remains comparable (0.29 vs 0.44 from 0.28 vs 0.44). These results indicates that one can hard obtain a consistent conformation for Aβ42 due to its instinct variety of Aβ42 conformation and dependence on the external solution condition, although both equilibrium conformations from S‐1 and S‐2 present part of structural features of Aβ42 conformational ensemble described by the “converging model” …”

Section: Resultsmentioning

confidence: 98%

“…In a word, the detailed folded structure of Aβ 42 monomer is not unique and the question on the transient structures of Aβ 42 monomer in aqueous environment remains open since different groups reported various results on Aβ 42 secondary structures. Nevertheless, the characteristic of conformational ensemble of full‐length Aβ 42 peptide is unanimous . That is, the Aβ 42 includes an unstructured N‐terminal region (residues 1–10), a central β‐rich hydrophobic core (residues 17–21), and a β‐strand dominated C‐terminus (residues 30–42), as well as consensually observed turn motif (residues 22–29).…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, the characteristic of conformational ensemble of full-length Aβ 42 peptide is unanimous. [20] That is, the Aβ 42 includes an unstructured N-terminal region (residues 1-10), a central β-rich hydrophobic core (residues [17][18][19][20][21], and a β-strand dominated C-terminus (residues 30-42), as well as consensually observed turn motif (residues [22][23][24][25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An Original Monomer Sampling from a Ready‐Made Aβ₄₂ NMR Fibril Suggests a Turn‐β‐Strand Synergetic Seeding Mechanism

et al. 2019

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Aggregation of amyloid beta (Aβ) is a central step of Alzheimer's disease. Aβ42 monomers are building blocks in the formation of both “on pathway” intermediate structures and “off pathway” oligomers. How to sample an Aβ monomer becomes a problem however due to the instinct of Aβ high flexibility and diversity as well as aggregation propensity. Currently, (1) most samplings focus on either the ready‐made helix‐rich 1Z0Q/1IYT NMR structure, or the completely extended conformation, but (2) few on a ready‐made Aβ NMR fibril (i. e., 2BEG). Here we compare the simulation results from sampling in scheme (1) with that in scheme (2), and find that the coil and β‐sheet contents in the 1Z0Q‐sampled system are comparable to the counterparts in the 2BEG‐sampled system, but with a large difference in simulation time and dynamics character. 1Z0Q‐sampled system not only takes several times longer than the 2BEG‐sampled one, and only β1‐seeding dynamics characteristic is observed probably due to far insufficient conformation transition in the limited simulation time. Two dynamics characteristics of Aβ42 folding observed experimentally, that either β1 region or β2 region aggregates first, reproduce in the present simulations for 2BEG‐sampled system however, suggesting a preferential sampling in the future simulation. In addition, a turn‐β‐strand synergetic seeding mechanism of aggregation is first proposed based on the trajectory analyses on the four regions of Aβ42 chain.

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“…APP, an integral membrane protein with roles in synapse formation and synaptic plasticity (Priller et al, 2006), undergoes posttranslational cleavage by presenilin-containing β- and γ-secretase complexes to generate amyloid-beta (Aβ) peptides of varying lengths (De Strooper and Annaert, 2000). Intrinsically disordered Aβ peptides adopt a random coil secondary structure and are cleaved into two common alloforms, Aβ 40 and Aβ 42 which account for approximately 90% and 5–10% of brain-wide Aβ production, respectively (Linh and Ha-Duong, 2015). Aβ 42 -biased imbalances in APP processing reduce Aβ clearance from neural tissues and consequently promote the self-aggregation of Aβ monomers into neurotoxic soluble Aβ oligomers and large insoluble Aβ plaques (Walsh and Selkoe, 2007).…”

Section: Neurodegenerative Disorders: Ipsc Models Induced Neural mentioning

confidence: 99%

The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders

Zhang

Zheng

2017

Progress in Neurobiology

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Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies.

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Exploring the Alzheimer amyloid-β peptide conformational ensemble: A review of molecular dynamics approaches

Cited by 72 publications

References 63 publications

Effect of pH on Aβ₄₂ Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

Effect of pH on Aβ₄₂ Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

An Original Monomer Sampling from a Ready‐Made Aβ₄₂ NMR Fibril Suggests a Turn‐β‐Strand Synergetic Seeding Mechanism

The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders

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Exploring the Alzheimer amyloid-β peptide conformational ensemble: A review of molecular dynamics approaches

Cited by 72 publications

References 63 publications

Effect of pH on Aβ42 Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

Effect of pH on Aβ42 Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

An Original Monomer Sampling from a Ready‐Made Aβ42 NMR Fibril Suggests a Turn‐β‐Strand Synergetic Seeding Mechanism

The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders

Contact Info

Product

Resources

About

Effect of pH on Aβ₄₂ Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

Effect of pH on Aβ₄₂ Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

An Original Monomer Sampling from a Ready‐Made Aβ₄₂ NMR Fibril Suggests a Turn‐β‐Strand Synergetic Seeding Mechanism