Comparison of the force fields on monomeric and fibrillar PHF6 of tau protein

Li, Yanchun; Peng, Xubiao

doi:10.1016/j.bpc.2021.106631

Cited by 7 publications

(5 citation statements)

References 54 publications

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“…Figure e shows that the CH−π distance in PHF6 and Pho-PHF6 systems are both larger than 0.4 nm, revealing that the inter-chain CH−π interaction does not exist in these two systems. A similar phenomenon was also seen in the previous MD simulation study investigating the fibrillization of PHF6 under multiple force fields . Taken together, our results reveal that Y310 phosphorylation hinders the PHF6 fibrillation by weakening Y310–Y310 π–π stacking and I308–Y310 CH−π interactions.…”

Section: Resultssupporting

confidence: 89%

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: Resultssupporting

confidence: 89%

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

et al. 2023

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“…Note that Charmm36m is the most suitable force field for tau simulation study according to benchmark studies. 39,61 In comparison with He et al's study, the structures of monomeric and dimeric R2 repeats in this study have higher β and turn contents and lower helix and coil contents. For the R2 monomer, we reported that the secondary structure contents of β-sheet, helix, turn, and coil were correspondingly 8, 2.8, 30.2, and 59%, which are quite different from those reported by He et al, which were 4.5, 9.2, 8.4, and 77.9%.…”

Section: ■ Discussioncontrasting

confidence: 52%

Phosphorylation at Ser289 Enhances the Oligomerization of Tau Repeat R2

Man

Han

et al. 2023

J. Chem. Inf. Model.

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In tauopathies such as Alzheimer's disease (AD), aberrant phosphorylation causes the dissociation of tau proteins from microtubules. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments and insoluble neurofibrillary tangles (NFTs). NFTs is a hallmark of AD, while oligomers are found to be the most toxic form of the tau aggregates. Therefore, understanding tau oligomerization with regard to abnormal phosphorylation is important for the therapeutic development of AD. In this study, we investigated the impact of phosphorylated Ser289, one of the 40 aberrant phosphorylation sites of full-length tau proteins, on monomeric and dimeric structures of tau repeat R2 peptides. We carried out intensive replica exchange molecular dynamics simulation with a total simulation time of up to 0.1 ms. Our result showed that the phosphorylation significantly affected the structures of both the monomer and the dimer. For the monomer, the phosphorylation enhanced ordered−disordered structural transition and intramolecular interaction, leading to more compactness of the phosphorylated R2 compared to the wild-type one. As to the dimer, the phosphorylation increased intermolecular interaction and β-sheet formation, which can accelerate the oligomerization of R2 peptides. This result suggests that the phosphorylation at Ser289 is likely to promote tau aggregation. We also observed a phosphorylated Ser289-Na + -phosphorylated Ser289 bridge in the phosphorylated R2 dimer, suggesting an important role of cation ions in tau aggregation. Our findings suggest that phosphorylation at Ser289 should be taken into account in the inhibitor screening of tau oligomerization.

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“…S5 ). Several factors are known to influence PHF6 fibril stability, such as electrostatic,

, and CH-

interactions ( 47 , 48 ), and these can vary between atomistic force fields ( 49 ), which predict different chain alignments within

-sheets ( 50 ). Our model suggests a free energetic bias toward antiparallel structures of

1.0 to

, so only a small change in force field interaction strengths is necessary to shift it.…”

Section: Resultsmentioning

confidence: 99%

Mapping the configurational landscape and aggregation phase behavior of the tau protein fragment PHF6

Pretti,

Shell

2023

Proc. Natl. Acad. Sci. U.S.A.

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The PHF6 (Val-Gln-Ile-Val-Tyr-Lys) motif, found in all isoforms of the microtubule-associated protein tau, forms an integral part of ordered cores of amyloid fibrils formed in tauopathies and is thought to play a fundamental role in tau aggregation. Because PHF6 as an isolated hexapeptide assembles into ordered fibrils on its own, it is investigated as a minimal model for insight into the initial stages of aggregation of larger tau fragments. Even for this small peptide, however, the large length and time scales associated with fibrillization pose challenges for simulation studies of its dynamic assembly, equilibrium configurational landscape, and phase behavior. Here, we develop an accurate, bottom-up coarse-grained model of PHF6 for large-scale simulations of its aggregation, which we use to uncover molecular interactions and thermodynamic driving forces governing its assembly. The model, not trained on any explicit information about fibrillar structure, predicts coexistence of formed fibrils with monomers in solution, and we calculate a putative equilibrium phase diagram in concentration-temperature space. We also characterize the configurational and free energetic landscape of PHF6 oligomers. Importantly, we demonstrate with a model of heparin that this widely studied cofactor enhances the aggregation propensity of PHF6 by ordering monomers during nucleation and remaining associated with growing fibrils, consistent with experimentally characterized heparin–tau interactions. Overall, this effort provides detailed molecular insight into PHF6 aggregation thermodynamics and pathways and, furthermore, demonstrates the potential of modern multiscale modeling techniques to produce predictive models of amyloidogenic peptides simultaneously capturing sequence-specific effects and emergent aggregate structures.

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Comparison of the force fields on monomeric and fibrillar PHF6 of tau protein

Cited by 7 publications

References 54 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

Phosphorylation at Ser289 Enhances the Oligomerization of Tau Repeat R2

Mapping the configurational landscape and aggregation phase behavior of the tau protein fragment PHF6

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