Mechanisms of melatonin binding and destabilizing the protofilament and filament of tau R3–R4 domains revealed by molecular dynamics simulation

Zhu, Lili; Gong, Yehong; Lju, Hao; Sun, Gongwu; Zhang, Qingwen; Qian, Zhenyu

doi:10.1039/d1cp03142b

Cited by 18 publications

(19 citation statements)

References 83 publications

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“…Mel preferentially binds to aromatic F23, followed by hydrophobic I26 and L27, while it has a similar binding affinity to the rest of the residues. Our previous study showed that the binding of Mel to a tau protein is dominated by H-bonding between Mel and the peptide backbone and is synergistically aided by other interactions [ 48 ]. Here, the binding of Mel to the hIAPP 20–29 octamer exhibits a similar behavior.…”

Section: Resultsmentioning

confidence: 99%

Melatonin Inhibits hIAPP Oligomerization by Preventing β-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation

Wang

Zhu

Song

et al. 2022

IJMS

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The pathogenesis of type 2 diabetes (T2D) is highly related to the abnormal self-assembly of the human islet amyloid polypeptide (hIAPP) into amyloid aggregates. To inhibit hIAPP aggregation is considered a promising therapeutic strategy for T2D treatment. Melatonin (Mel) was reported to effectively impede the accumulation of hIAPP aggregates and dissolve preformed fibrils. However, the underlying mechanism at the atomic level remains elusive. Here, we performed replica-exchange molecular dynamics (REMD) simulations to investigate the inhibitory effect of Mel on hIAPP oligomerization by using hIAPP20–29 octamer as templates. The conformational ensemble shows that Mel molecules can significantly prevent the β-sheet and backbone hydrogen bond formation of hIAPP20–29 octamer and remodel hIAPP oligomers and transform them into less compact conformations with more disordered contents. The interaction analysis shows that the binding behavior of Mel is dominated by hydrogen bonding with a peptide backbone and strengthened by aromatic stacking and CH–π interactions with peptide sidechains. The strong hIAPP–Mel interaction disrupts the hIAPP20–29 association, which is supposed to inhibit amyloid aggregation and cytotoxicity. We also performed conventional MD simulations to investigate the influence and binding affinity of Mel on the preformed hIAPP1–37 fibrillar octamer. Mel was found to preferentially bind to the amyloidogenic region hIAPP20–29, whereas it has a slight influence on the structural stability of the preformed fibrils. Our findings illustrate a possible pathway by which Mel alleviates diabetes symptoms from the perspective of Mel inhibiting amyloid deposits. This work reveals the inhibitory mechanism of Mel against hIAPP20–29 oligomerization, which provides useful clues for the development of efficient anti-amyloid agents.

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Section: Resultsmentioning

confidence: 99%

Melatonin Inhibits hIAPP Oligomerization by Preventing β-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation

Wang

Zhu

Song

et al. 2022

IJMS

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“…Molecular-simulation methods have long been used to study peptide aggregation, including both all-atom [ 16 , 17 , 18 ] and coarse-grained (CG) methodologies [ 19 ]. Of those, the methods based on CG models offer much longer time- and size-scales, including the possibility of simulating aggregation from scratch, even though this extension is achieved at the inevitable expense of modeling accuracy.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Aggregation of Biologically-Active Peptides with the UNRES Coarse-Grained Model

et al. 2022

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The UNited RESidue (UNRES) model of polypeptide chains was applied to study the association of 20 peptides with sizes ranging from 6 to 32 amino-acid residues. Twelve of those were potentially aggregating hexa- or heptapeptides excised from larger proteins, while the remaining eight contained potentially aggregating sequences, functionalized by attaching larger ends rich in charged residues. For 13 peptides, the experimental data of aggregation were used. The remaining seven were synthesized, and their properties were measured in this work. Multiplexed replica-exchange simulations of eight-chain systems were conducted at 12 temperatures from 260 to 370 K at concentrations from 0.421 to 5.78 mM, corresponding to the experimental conditions. The temperature profiles of the fractions of monomers and octamers showed a clear transition corresponding to aggregate dissociation. Low simulated transition temperatures were obtained for the peptides, which did not precipitate after incubation, as well as for the H-GNNQQNY-NH2 prion–protein fragment, which forms small fibrils. A substantial amount of inter-strand β-sheets was found in most of the systems. The results suggest that UNRES simulations can be used to assess peptide aggregation except for glutamine- and asparagine-rich peptides, for which a revision of the UNRES sidechain–sidechain interaction potentials appears necessary.

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“…1A). Although compounds with a high aromaticity value may have the ability to inhibit the aggregation of amyloid peptides, 6,[38][39][40] and many of them have relatively low inhibition potency. For example, we recently found that FeTPPS and FeTBAP have a better inhibitory effect on human islet amyloid polypeptide (hIAPP) fibril formation, 25,26 whereas, FeTMPyP, a structural analogue of FeTPPS and FeTBAP, is less effective, 26 indicating that the inhibitory effect of these ironporphyrins on hIAPP aggregation has a structure-activity relationship.…”

Section: Metalloporphyrins Inhibit Aβ 1-42 Fibrillationmentioning

confidence: 99%

“…Understanding the binding mode will help develop novel agents with anti-amyloid properties. 39,40 Therefore, answering the above questions will give a comprehensive knowledge to the selectivity of metalloporphyrins in stabilizing Aβ 1-42 monomers and the final different inhibitory effects on the aggregation of Aβ 1-42 .…”

Section: Metalloporphyrins Selectively Stabilize Aβ 1-42 Monomersmentioning

confidence: 99%

Structure and mechanism behind the inhibitory effect of water soluble metalloporphyrins on Aβ_1–42aggregation

Zhang

Liu

et al. 2022

Inorg. Chem. Front.

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Mechanisms of melatonin binding and destabilizing the protofilament and filament of tau R3–R4 domains revealed by molecular dynamics simulation

Abstract: Microsecond all-atom molecular dynamics simulations reveal that melatonin can destabilize the protofilament and filament of tau R3–R4 domains. Its influence on tau structure, binding kinetics and sites, and the disruptive mechanism are studied.

Cited by 18 publications

References 83 publications

Melatonin Inhibits hIAPP Oligomerization by Preventing β-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation

Melatonin Inhibits hIAPP Oligomerization by Preventing β-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation

Prediction of Aggregation of Biologically-Active Peptides with the UNRES Coarse-Grained Model

Structure and mechanism behind the inhibitory effect of water soluble metalloporphyrins on Aβ_1–42aggregation

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Mechanisms of melatonin binding and destabilizing the protofilament and filament of tau R3–R4 domains revealed by molecular dynamics simulation

Abstract: Microsecond all-atom molecular dynamics simulations reveal that melatonin can destabilize the protofilament and filament of tau R3–R4 domains. Its influence on tau structure, binding kinetics and sites, and the disruptive mechanism are studied.

Cited by 18 publications

References 83 publications

Melatonin Inhibits hIAPP Oligomerization by Preventing β-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation

Melatonin Inhibits hIAPP Oligomerization by Preventing β-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation

Prediction of Aggregation of Biologically-Active Peptides with the UNRES Coarse-Grained Model

Structure and mechanism behind the inhibitory effect of water soluble metalloporphyrins on Aβ1–42aggregation

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Structure and mechanism behind the inhibitory effect of water soluble metalloporphyrins on Aβ_1–42aggregation