The destructive mechanism of Aβ<sub>1–42</sub> protofibrils by norepinephrine revealed <i>via</i> molecular dynamics simulations

Gao, Duo; Wan, Jiaqian; Zou, Yu; Gong, Yehong; Dong, Xiaowei; Xu, Zhengdong; Tang, Jiaxing; Wei, Guanghong; Zhang, Qingwen

doi:10.1039/d2cp01754g

Cited by 10 publications

(9 citation statements)

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“…Norepinephrine binds to the Aβ dimer in its hydrophobic (K16-A21) and C-terminal (I31-V36) regions predominantly and also disrupts the global conformation of the Aβ protofibrillar structure by interacting with the N-terminal residues of the protofibrils. The disruptive potential is higher for deprotonated norepinephrine compared to the protonated one . The β-strands formed between the L12-H18 and L27-G33 regions of hIAPP, which stabilize the peptide self-assembly, are also hampered when norepinephrine preferentially interacts with the C-terminal β-prone region .…”

Section: Anti-amyloid Activity Of Non-polyphenolic Catechol Derivativesmentioning

confidence: 99%

“…The disruptive potential is higher for deprotonated norepinephrine compared to the protonated one. 78 The β-strands formed between the L12-H18 and L27-G33 regions of hIAPP, which stabilize the peptide self-assembly, are also hampered when norepinephrine preferentially interacts with the C-terminal β-prone region. 79 Similarly, norepinephrine destabilizes tau protofilaments by binding with the charged E338, E342, D348, D358, and E372 and aromatic Y310, P312, H374, and F378 residues through π−π stacking and hydrogen-bonding interactions.…”

Section: Anti-amyloid Activity Of Non-polyphenolic Catechol Derivativesmentioning

confidence: 99%

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Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

Roy

Paul

2023

J. Phys. Chem. B

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The onset of amyloidogenic diseases is associated with the misfolding and aggregation of proteins. Despite extensive research, no effective therapeutics are yet available to treat these chronic degenerative diseases. Targeting the aggregation of disease-specific proteins is regarded as a promising new approach to treat these diseases. In the past few years, rapid progress in this field has been made in vitro, in vivo, and in silico to generate potential drug candidates, ranging from small molecules to polymers to nanoparticles. Small molecular probes, mostly those derived from natural sources, have been of particular interest among amyloid inhibitors. Here, we summarize some of the most important natural small molecular probes which can inhibit the aggregation of Aβ, hIAPP, and α-syn peptides and discuss how their binding efficacy and preference for the peptides vary with their structure and conformation. This provides a comprehensive idea of the crucial factors which should be incorporated into the future design of novel drug candidates useful for the treatment of amyloid diseases.

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Section: Anti-amyloid Activity Of Non-polyphenolic Catechol Derivativesmentioning

confidence: 99%

Section: Anti-amyloid Activity Of Non-polyphenolic Catechol Derivativesmentioning

confidence: 99%

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

Roy

Paul

2023

J. Phys. Chem. B

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“…Furthermore, it provides the coordinates for the whole range of amino acids, i.e., 1–42, and so serves as one of the most relevant target structures for structure-based computational study. Certain studies included only pentamer units of protofibrils and so ignored the sites in the interfacial region. − Here we include the entire protofibril, and so the molecular docking algorithm could locate binding sites on the surface, in the core, and in the interfacial region (see Figure ). As the binding site details for DANIR-2c are not available, we performed a blind docking by including the entire fibril within the grid box.…”

Section: Computational Detailsmentioning

confidence: 99%

Computational Investigations into Two-Photon Fibril Imaging Using the DANIR-2c Probe

Murugan

Zaleśny

2023

J. Phys. Chem. B

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The design of novel fibril imaging molecules for medical diagnosis requires the simultaneous optimization of fibril-specific optical properties and binding specificity toward amyloid fibrils. Because of the possibility to monitor internal organs and deep tissues, the two-photon probes that can absorb in the infrared (IR) and near-IR (NIR) region with a significant two-photon absorption cross section are of immense interest. To contribute to this exploration of chemical compounds suitable for two-photon fibril imaging, we have computationally studied the one- and two-photon properties of a donor–acceptor-substituted DANIR-2c probe, which was used for in vivo detection of β-amyloid deposits using fluorescence spectroscopy. In particular, a multiscale computational approach was employed involving molecular docking, molecular dynamics, hybrid QM/MM molecular dynamics, and coupled-cluster/MM to study the binding of the studied probe to amyloid fibril and its one- and two-photon absorption properties in the fibrillar environment. Multiple binding sites are available for this probe in amyloid fibril, and the one corresponding to the largest binding affinity exhibits also the largest and experimentally meaningful two-photon absorption cross section, thus demonstrating the potential of the studied probe in two-photon microscopy.

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“…Razzokov and co-workers found that 3% of Met35 oxidation of an Aβ 11–42 pentamer led to a small destabilization in the structure of the pentamer and further increases of oxidation levels (9 and 15%) led to higher structural fluctuations and destabilization . MD simulation has also been used to study early steps of Aβ oligomer destabilization by the binding of a number of ligands. − …”

Section: Introductionmentioning

confidence: 99%

“… 56 MD simulation has also been used to study early steps of Aβ oligomer destabilization by the binding of a number of ligands. 57 − 60 …”

Section: Introductionmentioning

confidence: 99%

Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-Oxidation: A Molecular Dynamic Simulation Study

Maghsoodi

Martin

2023

ACS Omega

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Selective photosensitized oxidation of amyloid protein aggregates is being investigated as a possible therapeutic strategy for treating Alzheimer’s disease (AD). Photo-oxidation has been shown to degrade amyloid-β (Aβ) aggregates and ameliorate aggregate toxicity in vitro and reduce aggregate levels in the brains of AD animal models. To shed light on the mechanism by which photo-oxidation induces fibril destabilization, we carried out an all-atom molecular dynamics (MD) simulation to examine the effect of methionine (Met35) oxidation on the conformation and stability of a β-sheet-rich Aβ9–40 protofibril. Analyses of up to 1 μs simulations showed that the oxidation of the Met35 residues, which resulted in the addition of hydrophilic oxygens in the fibril core, reduced the overall conformational stability of the protofibril. Specifically, Met35 disrupted the hydrophobic interface that stabilizes the stacking of the two hexamers that comprise the protofibril. The oxidized protofibril is more solvent exposed and exhibits more backbone flexibility. However, the protofibril retained the underlying U-shaped architecture of each peptide upon oxidation, and although some loss of β-sheets occurred, a significant portion remained. Our simulation results are thus consistent with our experimental observation that photo-oxidation of Aβ40 fibril resulted in the dis-agglomeration and fragmentation of Aβ fibrils but did not cause complete disruption of the fibrillar morphology or β-sheet structures. The partial destabilization of Aβ aggregates supports the further development of photosensitized platforms for the targeting and clearing of Aβ aggregates as a therapeutic strategy for treating AD.

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The destructive mechanism of Aβ_1–42 protofibrils by norepinephrine revealed via molecular dynamics simulations

Abstract: Amyloid-β (Aβ) fibrillary plaques represent the main hallmarks of Alzheimer’s disease (AD), in addition to tau neurofibrillary tangles. Disrupting early-formed Aβ protofibril is considered as one of the primary therapeutic...

Cited by 10 publications

References 58 publications

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

Computational Investigations into Two-Photon Fibril Imaging Using the DANIR-2c Probe

Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-Oxidation: A Molecular Dynamic Simulation Study

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The destructive mechanism of Aβ1–42 protofibrils by norepinephrine revealed via molecular dynamics simulations

Abstract: Amyloid-β (Aβ) fibrillary plaques represent the main hallmarks of Alzheimer’s disease (AD), in addition to tau neurofibrillary tangles. Disrupting early-formed Aβ protofibril is considered as one of the primary therapeutic...

Cited by 10 publications

References 58 publications

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides

Computational Investigations into Two-Photon Fibril Imaging Using the DANIR-2c Probe

Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-Oxidation: A Molecular Dynamic Simulation Study

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Product

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The destructive mechanism of Aβ_1–42 protofibrils by norepinephrine revealed via molecular dynamics simulations