Role of the Region 23-28 in A&amp;#946; Fibril Formation: Insights from Simulations of the Monomers and Dimers of Alzheimers Peptides A&amp;#946;40 and A&amp;#946;42

Melquiond, Adrien; Dong, Xiao; Mousseau, Normand; Derreumaux, Philippe

doi:10.2174/156720508784533330

Cited by 95 publications

(112 citation statements)

References 72 publications

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“…Second, the polymorphic tubular-like shape Aβ 42 fibril models studied here reveal that the N-terminal of the Aβ peptide plays a crucial role in the protofilament assembly. So far, it was believed that the disordered N-terminal segment is not involved in fibril formation because of its high flexibility, although earlier studies suggested that the N-terminal segments may form β-sheet in parallel orientation (24,25), which is also observed here (SI Text and Fig. S10).…”

Section: Populations and Relative Stabilities For Aβ 42 Tubular Modelsupporting

confidence: 64%

Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH

Miller

Tsai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Recent cryoEM density maps of A β 42 fibrils obtained at low pH revealed two protofilaments winding around a hollow core raising the question if such tubular structures also exist at physiological pH. Based on the cryoEM measurements and on NMR data, we probe amyloid fibril organizations corresponding to the observed cryoEM density map. Our study demonstrates that the tubular A β 42 fibril models exist at both acidic and physiological pH; however, the relative populations of the polymorphic models shift with pH. At acidic pH, the hollow core model exhibits higher population than the other models; at physiological pH, although it is less populated compared to the other models, structurally, it is stable and represents 8% of the population. We observe that only models with C termini facing the external surface of the fibril retain the hollow core under acidic and physiological conditions with dimensions similar to those observed by cryoEM; on the other hand, the hydrophobic effect shrinks the tubular cavity in the alternative organization. The existence of the hollow core fibril at physiological pH emphasizes the need to examine toxic effects of minor oligomeric species with unique organizations.

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Section: Populations and Relative Stabilities For Aβ 42 Tubular Modelsupporting

confidence: 64%

Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH

Miller

Tsai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The binding of curcumin and Congo red revealed that in some of the complexes, the ligands remain bound during the 80 ns MD at 300 K. 58 Though Tyr10, Met35, and the CHC region are identified by our study, it is not surprising to observe differences because it is well-known that the configurations of Aβ1−42 monomer and dimer are different. 17,23,59 Finally, we can compare our results with implicit solvent MD simulations of Aβ1−42 monomer interacting with carnosine, a dipeptide naturally occurring in the brain and rescuing cells from Aβ-induced toxicity. 60 Using a total MD trajectory of 3 μs, carnosine was found to interact transiently by salt bridges with charged residues Arg5, Lys16, and Lys28, and the CHC and flanked residues.…”

Section: ■ Discussionmentioning

confidence: 94%

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Zhang

et al. 2013

ACS Chem. Neurosci.

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Aggregation of the amyloid β protein (Aβ) peptide with 40 or 42 residues is one key feature in Alzheimer's disease (AD). The 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp) molecule was reported to alter Aβ self-assembly and reduce toxicity. Though nuclear magnetic resonance experiments and various simulations provided atomic information about the interaction of NQTrp with Aβ peptides spanning the regions of residues 12−28 and 17−42, none of these studies were conducted on the fulllength Aβ1−42 peptide. To this end, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1−42 dimer with two NQTrp molecules in explicit solvent, by using a force field known to fold diverse proteins correctly. The interactions between NQTrp and Aβ1−42, which change the Aβ interface by reducing most of the intermolecular contacts, are found to be very dynamic and multiple, leading to many transient binding sites. The most favorable binding residues are Arg5, Asp7, Tyr10, His13, Lys16, Lys18, Phe19/Phe20, and Leu34/Met35, providing therefore a completely different picture from in vitro and in silico experiments with NQTrp with shorter Aβ fragments. Importantly, the 10 hot residues that we identified explain the beneficial effect of NQTrp in reducing both the level of Aβ1−42 aggregation and toxicity. Our results also indicate that there is room to design more efficient drugs targeting Aβ1−42 dimer against AD.

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“…36,57,58 In particular, Urbanc et al showed that the central hydrophobic cluster ͑residues 17-21͒ plays a dominant role in A␤ 1-40 aggregation. 58 However, given a complexity of A␤ oligomer assembly, studies with explicit solvent models will be needed to ascertain the role of the Nt region in aggregation.…”

Section: B Structural Properties Of A␤ Dimers and Tetramers Are Similarmentioning

confidence: 99%

Globular state in the oligomers formed by Aβ peptides

Kim

Takeda

Klimov

2010

The Journal of Chemical Physics

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Replica exchange molecular dynamics and implicit solvent model are used to study two oligomeric species of A␤ peptides, dimer and tetramer, which are typically observed in in vitro experiments. Based on the analysis of free energy landscapes, density distributions, and chain flexibility, we propose that the oligomer formation is a continuous transition occurring without metastable states. The density distribution computations suggest that A␤ oligomer consists of two volume regionsthe core with fairly flat density profile and the surface layer with rapidly decreasing density. The core is mostly formed by the N-terminal residues, whereas the C-terminal tends to occur in the surface layer. Lowering the temperature results in the redistribution of peptide atoms from the surface layer into the core. Using these findings, we argue that A␤ oligomer resembles polymer globule in poor solvent. A␤ dimers and tetramers are found to be structurally similar suggesting that the conformations of A␤ peptides do not depend on the order of small oligomers.

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Role of the Region 23-28 in Aβ Fibril Formation: Insights from Simulations of the Monomers and Dimers of Alzheimers Peptides Aβ40 and Aβ42

Cited by 95 publications

References 72 publications

Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH

Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Globular state in the oligomers formed by Aβ peptides

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Role of the Region 23-28 in A&#946; Fibril Formation: Insights from Simulations of the Monomers and Dimers of Alzheimers Peptides A&#946;40 and A&#946;42

Cited by 95 publications

References 72 publications

Hollow core of Alzheimer’s A β 42 amyloid observed by cryoEM is relevant at physiological pH

Hollow core of Alzheimer’s A β 42 amyloid observed by cryoEM is relevant at physiological pH

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Globular state in the oligomers formed by Aβ peptides

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Role of the Region 23-28 in Aβ Fibril Formation: Insights from Simulations of the Monomers and Dimers of Alzheimers Peptides Aβ40 and Aβ42

Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH

Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH