Interactions of a multifunctional di-triazole derivative with Alzheimer's Aβ<sub>42</sub>monomer and Aβ<sub>42</sub>protofibril: a systematic molecular dynamics study

Kaur, Anupamjeet; Shuaib, Suniba; Goyal, Deepti; Goyal, Bhupesh

doi:10.1039/c9cp04775a

Cited by 26 publications

(14 citation statements)

References 105 publications

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“…62,63 Our previous REMD simulations showed that norepinephrine can inhibit Aβ dimerization by binding to central (16KLVFFA21) and C-terminal (31IIGLMV36) hydrophobic sites. 64 Increasing number of MD simulation studies revealed that small molecules (including morin, 65 NQTrp, 66 12-crown-4 ether, 67 EGCG, 68 wgx-50, 69 dihydrochalcone, 70 a resveratrol and clioquinol hybrid compound, 71 caffeine and ditriazole derivative 72,73 ) preferentially bind to the hydrophobic cavity of U-shaped Aβ protofibrils/fibrils and destroy their structures. Recently, we have explored the disruptive mechanism of recently resolved LS-shaped Aβ 42 protofibril by EGCG 57 and catechin 74 and found that those In spite of extensive experimental and computational studies, the atomic mechanism of dopamine in disaggregating preformed Aβ fibrils and inhibiting Aβ aggregation remains largely unclear.…”

Section: ■ Introductionmentioning

confidence: 99%

A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation

Chen

Zhan

et al. 2021

ACS Chem. Neurosci.

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Fibrillary aggregates of amyloid-β (Aβ) are the pathological hallmark of Alzheimer’s disease (AD). Clearing Aβ deposition or inhibiting Aβ aggregation is a promising approach to treat AD. Experimental studies reported that dopamine (DA), an important neurotransmitter, can inhibit Aβ aggregation and disrupt Aβ fibrils in a dose-dependent manner. However, the underlying molecular mechanisms still remain mostly elusive. Herein, we investigated the effect of DA on Aβ42 protofibrils at three different DA-to-Aβ molar ratios (1:1, 2:1, and 10:1) using all-atom molecular dynamics simulations. Our simulations demonstrate that protonated DA at a DA-to-Aβ ratio of 2:1 exhibits stronger Aβ protofibril disruptive capacity than that at a molar-ratio of 1:1 by mostly disrupting the F4-L34-V36 hydrophobic core. When the ratio of DA-to-Aβ increases to 10:1, DA has a high probability to bind to the outer surface of protofibril and has negligible effect on the protofibril structure. Interestingly, at the same DA-to-Aβ ratio (10:1), a mixture of protonated (DA+) and deprotonated (DA0) DA molecules significantly disrupts Aβ protofibrils by the binding of DA0 to the F4-L34-V36 hydrophobic core. Replica-exchange molecular dynamics simulations of Aβ42 dimer show that DA+ inhibits the formation of β-sheets, K28-A42/K28-D23 salt-bridges, and interpeptide hydrophobic interactions and results in disordered coil-rich Aβ dimers, which would inhibit the subsequent fibrillization of Aβ. Further analyses reveal that DA disrupts Aβ protofibril and prevents Aβ dimerization mostly through π–π stacking interactions with residues F4, H6, and H13, hydrogen bonding interactions with negatively charged residues D7, E11, E22 and D23, and cation−π interactions with residues R5. This study provides a complete picture of the molecular mechanisms of DA in disrupting Aβ protofibril and inhibiting Aβ aggregation, which could be helpful for the design of potent drug candidates for the treatment/intervention of AD.

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Section: ■ Introductionmentioning

confidence: 99%

A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation

Chen

Zhan

et al. 2021

ACS Chem. Neurosci.

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“…Until now, an effective treatment for AD does not yet exist. It is crucial to find effective inhibitors for the treatment of AD. − A large number of experimental studies reported that several different types of potential inhibitors, including nanoparticles, , short peptides, − small molecules, , multitarget-directed ligands, − and antibodies, , are able to dissociate Aβ fibrils and/or inhibit Aβ aggregation. Inspired by those experimental studies, several computational groups investigated the inhibitory mechanisms − using MD simulations.…”

Section: Introductionmentioning

confidence: 99%

Serotonin and Melatonin Show Different Modes of Action on Aβ₄₂ Protofibril Destabilization

Gong

Zhan

Zou

et al. 2021

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is associated with the aberrant self-assembly of amyloid-β (Aβ) protein into fibrillar deposits. The disaggregation of Aβ fibril is believed as one of the major therapeutic strategies for treating AD. Previous experimental studies reported that serotonin (Ser), one of the indoleamine neurotransmitters, and its derivative melatonin (Mel) are able to disassemble preformed Aβ fibrils. However, the fibril-disruption mechanisms are unclear. As the first step to understand the underlying mechanism, we investigated the interactions of Ser and Mel molecules with the LS-shaped Aβ 42 protofibril by performing a total of nine individual 500 ns all-atom molecular dynamics (MD) simulations. The simulations demonstrate that both Ser and Mel molecules disrupt the local β-sheet structure, destroy the salt bridges between K28 side chain and A42 COO − , and consequently destabilize the global structure of Aβ 42 protofibril. The Mel molecule exhibits a greater binding capacity than the Ser molecule. Intriguingly, we find that Ser and Mel molecules destabilize Aβ 42 protofibril through different modes of action. Ser preferentially binds with the aromatic residues in the Nterminal region through π−π stacking interactions, while Mel binds not only with the N-terminal aromatic residues but also with the C-terminal hydrophobic residues via π−π and hydrophobic interactions. This work reveals the disruptive mechanisms of Aβ 42 protofibril by Ser and Mel molecules and provides useful information for designing drug candidates against AD.

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“…However, in our opinion CHC will remain as the most probable target of BSBs and within it both phenylalanines 19 and 20 are supposedly crucial for the action of inhibitor molecules. This notion is also substantiated by the results obtained by use of different fibril models and small non‐peptide molecule inhibitors 52‐56 …”

Section: Discussionmentioning

confidence: 62%

β‐sheet breakers with consecutive phenylalanines: Insights into mechanism of dissolution of β‐amyloid fibrils

2021

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β‐sheet breakers (BSB) constitute a class of peptide inhibitors of amyloidogenesis, a process which is a hallmark of many diseases called amyloidoses, including Alzheimer's disease (AD); however, the molecular details of their action are still not fully understood. Here we describe the results of the computational investigation of the three BSBs, iaβ6 (LPFFFD), iaβ5 (LPFFD), and iaβ6_Gly (LPFGFD), in complex with the fibril model of Aβ42 and propose the kinetically probable mechanism of their action. The mechanism involves the binding of BSB to the central hydrophobic core (CHC) region (LVFFA) of Aβ fibril and the π‐stacking of its Phe rings both internally and with the Aβ fibril. In the process, the Aβ fibril undergoes distortion accumulating on the side of chain A (located on the odd tip of the fibril). In a single replica of extended molecular dynamics run of one of the iaβ6 poses, the distortion concludes in a dissociation of chain A from the fibril model of Aβ42. Altogether, we postulate that including consecutive Phe residues into BSBs docked around Phe 20 in the CHC region of Aβ42 improve their potency for dissolution of fibrils.

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Interactions of a multifunctional di-triazole derivative with Alzheimer's Aβ₄₂monomer and Aβ₄₂protofibril: a systematic molecular dynamics study

Abstract: The molecular dynamics simulations results highlighted that the multi-target-directed ligand 6n stabilizes the native α-helix conformation of the Aβ42 monomer and induces a sizable destabilization in the Aβ42 protofibril structure.

Cited by 26 publications

References 105 publications

A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation

A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation

Serotonin and Melatonin Show Different Modes of Action on Aβ₄₂ Protofibril Destabilization

β‐sheet breakers with consecutive phenylalanines: Insights into mechanism of dissolution of β‐amyloid fibrils

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Interactions of a multifunctional di-triazole derivative with Alzheimer's Aβ42monomer and Aβ42protofibril: a systematic molecular dynamics study

Abstract: The molecular dynamics simulations results highlighted that the multi-target-directed ligand 6n stabilizes the native α-helix conformation of the Aβ42 monomer and induces a sizable destabilization in the Aβ42 protofibril structure.

Cited by 26 publications

References 105 publications

A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation

A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aβ Protofibrils and Inhibiting Aβ Aggregation

Serotonin and Melatonin Show Different Modes of Action on Aβ42 Protofibril Destabilization

β‐sheet breakers with consecutive phenylalanines: Insights into mechanism of dissolution of β‐amyloid fibrils

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Interactions of a multifunctional di-triazole derivative with Alzheimer's Aβ₄₂monomer and Aβ₄₂protofibril: a systematic molecular dynamics study

Serotonin and Melatonin Show Different Modes of Action on Aβ₄₂ Protofibril Destabilization