Molecular Dynamics Simulations of the Tau Amyloid Fibril Core Dimer at the Surface of a Lipid Bilayer Model: I. In Alzheimer’s Disease

Nguyen, Phuong H.; Derreumaux, Philippe

doi:10.1021/acs.jpcb.2c02836

Cited by 12 publications

(15 citation statements)

References 59 publications

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“…Interestingly, a recent MD simulation study has revealed that the PHF6 motif (V306-K311) of an R3−R4 tau dimer associated with Alzheimer's disease bears high β-sheet probability even when the dimer mostly remains in a random coil-rich state when it is absorbed on the membrane. 71 Then, the β-sheet probability of residues V309−Y310 in β1, K317−T319 in β2, V350−S352 in β6, and K375−T377 in β8 is significantly decreased in the Tau + QE system (the result for β fragments is shown in Figure S1a). Remarkably, the disruption of the β-sheet in the PHF6 motif can reduce the membrane binding, impede the protein/ phospholipid complex formation, and abrogate its uptake by primary neurons in hippocampus, thus weakening tau toxicity.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

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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Section: ■ Results and Discussionmentioning

confidence: 98%

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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“…The binding of Aβ to ganglioside-containing membranes also plays an important role in the pathogenesis of AD . Interactions of Aβ species and other amyloid proteins with membrane cell are very transient and oligomer-size dependent. ,− Helical intermediates appear to be particularly important in membrane-catalyzed amyloid formation …”

Section: Resultsmentioning

confidence: 99%

“…65 Interactions of Aβ species and other amyloid proteins with membrane cell are very transient and oligomer-size dependent. 62,[66][67][68] Helical intermediates appear to be particularly important in membrane-catalyzed amyloid formation. 69 Extending their cubic lattice to interactions of Aβ42 with hydrophilic and hydrophobic surfaces, Li et al showed that, consistent with experimental studies, an increase in roughness slows down fibril formation, and this process becomes inhibited at a very highly level of roughness.…”

Section: Protein Self-assembly Near In Vivo Conditionsmentioning

confidence: 99%

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

2022

Self Cite

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Understanding the atomistic resolution changes during the self-assembly of amyloid peptides or proteins is important to develop compounds or conditions to alter the aggregation pathways and suppress the toxicity, and potentially aid in the development of drugs. However, the complexity of protein aggregation and the transient order/disorder of oligomers along pathways to fibril are very challenging. In this perspective, we discuss computational studies of amyloid polypeptides carried out under various conditions, including conditions closely mimicking in vivo, and point out the challenges in obtaining physiologically-relevant results, focusing mainly on the amyloid-beta Aβ peptides. 1.IntroductionAmyloid fibril with a cross β-structure and intermolecular H-bonds parallel to the long fibril axis is a hallmark of many sequences differing in amino acid length and composition involved in neurogenerative diseases. These involve Aβ and tau proteins in Alzheimer's disease (AD), α-synuclein in Parkinson disease, superoxide dismutase 1 (SOD1) protein in amyotrophic lateral sclerosis, transthyretin protein in cardiac and systemic amyloidosis, prion protein in prion disease, and human islet amyloid polypeptide (hIAPP) in type 2 diabetes, among others.Fragments of these proteins form fibrils as well, which represent ideal systems for computational studies. 1 In this perspective, we mainly focus on the Aβ peptides. Results and Discussion Protein self-assembly under quiescent solution conditionsThe aggregation kinetics of amyloid proteins in aqueous solution, as measured by Thioflavin T (ThT) fluorescence assays, displays a sigmoidal curve with a lag-phase where monomers undergo conformational conversion and self-assemble into oligomers until the growth phase where the fibril elongates. This is followed by the saturation phase where the system is in equilibrium between fibrils and a low concentration of monomers. Aggregation is described by microscopic events involving primary nucleation, elongation and dissociation of a fibril by one monomer, and secondary (fibril fragmentation and fibril surface-catalyzed) nucleation. The rates of the different microscopic processes are obtained by fitting the experimental aggregation kinetic curves using multiple initial monomer concentrations. It was shown the aggregation kinetics is sensitive to variations in temperature, pH, protein concentration, ionic strength, and the presence of cofactors and preformed aggregates. 2 General questions probing amyloid fibril formation of short peptides adopting straight β-strands in the bulk solution were addressed by on-lattice models and Monte Carlo simulations. It was demonstrated that the energy difference between the monomeric native state and the fibril-prone (N*) state, and therefore the population of the ensemble of N* structures in the full spectrum of conformations, are the major determinants of the time for fibril formation. 3,4 Based on a cubic lattice that considers the formation of H-bonds and pairwise side chain interactions, 5 and replic...

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“…PHF6 lies at the beginning of the third repeat domain (R3) of tau and is believed to play a critical role in promoting tau aggregation 30−32 and the interactions of tau with the membranes. 33,34 It displays a strong self-assembling tendency to form fibrils similar to those formed by full-length tau. 35,36 Therefore, PHF6 is extensively used as a simple model system for studying tau aggregation.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Among them, Try-310 (Y310) has received predominant attention since it is located within the aggregation-prone hexapeptide 306 VQIVYK 311 (PHF6). PHF6 lies at the beginning of the third repeat domain (R3) of tau and is believed to play a critical role in promoting tau aggregation − and the interactions of tau with the membranes. , It displays a strong self-assembling tendency to form fibrils similar to those formed by full-length tau. , Therefore, PHF6 is extensively used as a simple model system for studying tau aggregation . Recent studies demonstrated that Y310 phosphorylation could decrease the propensity of PHF6 sequence to form fibrils and delay tau aggregation. , Santa-María et al investigated the regions of tau that participate in PHF formation and found that PHF6 could fibrillize in the absence of inducers, and the phosphorylation of Y310 abolished the formation of PHF6 fibrils .…”

Section: Introductionmentioning

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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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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Molecular Dynamics Simulations of the Tau Amyloid Fibril Core Dimer at the Surface of a Lipid Bilayer Model: I. In Alzheimer’s Disease

Cited by 12 publications

References 59 publications

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

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

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

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

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