Mechanistic insight into the disruption of Tau R3–R4 protofibrils by curcumin and epinephrine: an all-atom molecular dynamics study

Zou, Yu; Qi, Bote; Tan, Jingwang; Sun, Yunxiang; Gong, Yehong; Zhang, Qingwen

doi:10.1039/d2cp02353a

Cited by 16 publications

(28 citation statements)

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“…Two aromatic rings were considered to have π−π stacking interactions when their centroid distance was within 0.65 nm. 60,61 The CH−π interaction could only possibly exist when the "CH−π distance" was below 0.4 nm. 62 Graphical analysis and structure visualization were performed using the VMD software.…”

Section: ■ Methodsmentioning

confidence: 99%

“…An atomic contact was defined when two aliphatic carbon atoms were within 0.54 nm or any other two heavy atoms were within 0.46 nm. Two aromatic rings were considered to have π–π stacking interactions when their centroid distance was within 0.65 nm. , The CH−π interaction could only possibly exist when the “CH−π distance” was below 0.4 nm . Graphical analysis and structure visualization were performed using the VMD software …”

Section: Methodsmentioning

confidence: 99%

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Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6

et al. 2023

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Abnormal aggregation of the microtubule-associated protein tau into intracellular fibrillary inclusions is characterized as the hallmark of tauopathies, including Alzheimer’s disease and chronic traumatic encephalopathy. The hexapeptide 306VQIVYK311 (PHF6) of R3 plays an important role in the aggregation of tau. Recent experimental studies reported that phosphorylation of residue tyrosine 310 (Y310) could decrease the propensity of PHF6 to form fibrils and inhibit tau aggregation. However, the underlying inhibitory mechanism is not well understood. In this work, we systematically investigated the influences of phosphorylation on the conformational ensembles and oligomerization dynamics of PHF6 by performing extensive all-atom molecular dynamics (MD) simulations. Our replica exchange MD simulations demonstrate that Y310 phosphorylation could effectively suppress the formation of β-structure and shift PHF6 oligomers toward coil-rich aggregates. The interaction analyses show that hydrogen bonding and hydrophobic interactions among PHF6 peptides, as well as Y310–Y310 π–π stacking and I308–Y310 CH−π interactions, are weakened by phosphorylation. Additional microsecond MD simulations show that Y310 phosphorylation could inhibit the oligomerization of PHF6 by preventing the formation of large β-sheet oligomers and multi-layer β-sheet aggregates. This study provides mechanistic insights into the phosphorylation-inhibited tau aggregation, which may be helpful for the in-depth understanding of the pathogenesis of tauopathies.

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Section: ■ Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6

et al. 2023

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“…In our study, we chose a pentamer as a protofibril model, since Zou et al found that a pentamer is the smallest stable protofibril associated with CTE. 77 The pentamer was built based on a CTE-related R3−R4 tau fibril structure (PDB ID: 6NWP). The three-dimensional structures of QE and GA were taken from the PubChem Compound Database (QE CID = 5280343; GA CID = 370).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…We performed all-atom MD simulations on three systems: CTE-related R3–R4 tau protofibril alone, CTE-related R3–R4 tau protofibril + QE, and CTE-related R3–R4 tau protofibril + GA. In our study, we chose a pentamer as a protofibril model, since Zou et al found that a pentamer is the smallest stable protofibril associated with CTE . The pentamer was built based on a CTE-related R3–R4 tau fibril structure (PDB ID: 6NWP).…”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanism in the Disruption of Chronic Traumatic Encephalopathy-Related R3–R4 Tau Protofibril by Quercetin and Gallic Acid: Similarities and Differences

Tang

Zou

Gong

et al. 2023

ACS Chem. Neurosci.

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Chronic traumatic encephalopathy (CTE) is a unique progressive neurodegenerative tauopathy pathologically related to the aggregation of the tau protein to neurofibrillary tangles. Disrupting tau oligomers (protofibril) is a promising strategy to prevent CTE. Quercetin (QE) and gallic acid (GA), two polyphenol small molecules abundant in natural crops, were proved to inhibit recombinant tau and the R3 fragment of human full-length tau in vitro. However, their disruptive effect on CTE-related protofibril and the underlying molecular mechanism remain elusive. Cryo-electron microscopy resolution reveals that the R3-R4 fragment of tau forms the core of the CTE-related tau protofibril. In this study, we conducted extensive all-atom molecular dynamics simulations on CTE-related R3-R4 tau protofibril with and without QE/GA molecules. The results disclose that both QE and GA can disrupt the global structure of the protofibril, while GA shows a relatively strong effect. The binding sites, exact binding patterns, and disruptive modes for the two molecules show similarities and differences. Strikingly, both QE and GA can insert into the hydrophobic cavity of the protofibril, indicating they have the potential to compete for the space in the cavity with aggregation cofactors unique to CTE-related protofibril and thus impede the further aggregation of the tau protein. Due to relatively short time scale, our study captures the early disruptive mechanism of CTE-related R3–R4 tau protofibril by QE/GA. However, our research does provide valuable knowledge for the design of supplements or drugs to prevent or delay the development of CTE.

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“…Tau and the other disease-forming aggregates have been shown to evolve through the liquid -solid and liquid -liquid phase transition of the proteins 5 . The conformational dynamics of the tau fibrils has a significant role in the pathogenesis of tauopathy as shown from the earlier molecular dynamics studies [6][7][8][9][10][11][12][13] . Owing to the failure of the amyloid-beta as the drug-binding target for Alzheimer's disease (AD), the current focus is mostly on the tau fibrils and their underlying conformational changes in regulating the concurrent tauopathies 14,15 .…”

Section: Introductionmentioning

confidence: 98%

Interaction of the Tau fibrils with the neuronal membrane^†

Chowdhury

Paul

Bhargava

2022

Preprint

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Tau proteins are gaining a lot of interest recently due to their active role in causing a range of tauopathies. Molecular mechanisms underlying the tau interaction with the neuronal membrane are hitherto unknown and difficult to characterize using conventional experimental methods. Starting from the cryo-EM structure of the tau fibrils, we have used atomistic molecular dynamics simulations to model the interaction between the fibril and neuronal membrane, with explicit solvation. The dynamics and structural characteristics of the tau fibril with the neuronal membrane are compared to the tau fibril in the aqueous phase to corroborate the effect of the neuronal membrane on the tau structure. The tau fibrils are in general more compact in the presence of neuronal membrane compared to their structure in the water medium. We find that the number of β-sheet residues of the tau fibrils are different in the case of two polymorphs, paired helical filament and straight filaments (PHF and SF) in the two media. PHF is found to approach closer to the neuronal membrane than the SF. The negatively charged lipids in the neuronal membrane are found to mediate the tau-neuronal membrane binding. Our study initiates the understanding of tau conformational ensemble in the presence of neuronal membrane and sheds light on the significant tau - membrane interactions. The simulation times of our report might limit the conformational sampling required to observe membrane permeation, nevertheless it provides significant insights into fibril - neuronal membrane interactions.

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Mechanistic insight into the disruption of Tau R3–R4 protofibrils by curcumin and epinephrine: an all-atom molecular dynamics study

Abstract: The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the...

Cited by 16 publications

References 75 publications

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6

Molecular Mechanism in the Disruption of Chronic Traumatic Encephalopathy-Related R3–R4 Tau Protofibril by Quercetin and Gallic Acid: Similarities and Differences

Interaction of the Tau fibrils with the neuronal membrane^†

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Mechanistic insight into the disruption of Tau R3–R4 protofibrils by curcumin and epinephrine: an all-atom molecular dynamics study

Abstract: The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the...

Cited by 16 publications

References 75 publications

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6

Molecular Mechanism in the Disruption of Chronic Traumatic Encephalopathy-Related R3–R4 Tau Protofibril by Quercetin and Gallic Acid: Similarities and Differences

Interaction of the Tau fibrils with the neuronal membrane†

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Resources

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Interaction of the Tau fibrils with the neuronal membrane^†