The F19W mutation reduces the binding affinity of the transmembrane Aβ<sub>11–40</sub> trimer to the membrane bilayer

Tran, Thanh Thuy; Pan, Feng; Tran, Linh; Roland, Christopher; Sagui, Celeste

doi:10.1039/d0ra08837d

Cited by 2 publications

(1 citation statement)

References 90 publications

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“…They found that van der Waals interactions are the principal driving force for the binding between the trimer and lipid membrane, resulting in the penetration of the trimer in the bilayers. On the other hand, A21G [ 71 ] and F19W [ 72 ] mutations in the trimer decrease the presence of ASP23-LYS28 salt bridge, which leads to a destabilization of the trimer within the DPPC membranes. These mutations of Aβ 11-40 trimers implied a lower aggregation tendency and reduced stability within the membrane compared to wild-type truncated trimer.…”

Section: Why Does Aβ Peptide Perturb Membrane Integrity?mentioning

confidence: 99%

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

Boopathi

Poma

Garduño‐Juárez

2021

IJMS

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Amyloid beta (Aβ) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer’s disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aβ peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aβ experiments, as it allows to explore the binding mechanism between metal ions and Aβ oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aβ peptides. Aβ oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Ohydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aβ binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aβ. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aβ dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.

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Section: Why Does Aβ Peptide Perturb Membrane Integrity?mentioning

confidence: 99%

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

Boopathi

Poma

Garduño‐Juárez

2021

IJMS

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Molecular mechanisms of direct and indirect interplay between amyloid β42 oligomer and characteristic lipids

et al. 2022

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The F19W mutation reduces the binding affinity of the transmembrane Aβ_11–40 trimer to the membrane bilayer

Abstract: Dominant conformations of F19W 3Aβ11–40 immersed in transmembrane DPPC lipid bilayer submerged in aqueous solution.

Cited by 2 publications

References 90 publications

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

Molecular mechanisms of direct and indirect interplay between amyloid β42 oligomer and characteristic lipids

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The F19W mutation reduces the binding affinity of the transmembrane Aβ11–40 trimer to the membrane bilayer

Abstract: Dominant conformations of F19W 3Aβ11–40 immersed in transmembrane DPPC lipid bilayer submerged in aqueous solution.

Cited by 2 publications

References 90 publications

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

Molecular mechanisms of direct and indirect interplay between amyloid β42 oligomer and characteristic lipids

Contact Info

Product

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About

The F19W mutation reduces the binding affinity of the transmembrane Aβ_11–40 trimer to the membrane bilayer