Unravelling the destabilization potential of ellagic acid on α-synuclein fibrils using molecular dynamics simulations

Kaur, Opinder; Kaur, Anupamjeet; Goyal, Deepti; Goyal, Bhupesh

doi:10.1039/d2cp06006j

Cited by 1 publication

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References 98 publications

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“…Recently, the disruption mechanism of α-Syn decamer comprising two intertwined pentamers (PDB ID: 6CU7) by Ellagic acid has been investigated using MD simulations. 30 The computational studies investigating the effect of inhibitors on the destabilization of oligomers of different sizes are worthy for gaining insights into the discovery of new inhibitors of α-Syn aggregation and protofibril destabilization in PD.…”

Section: Introductionmentioning

confidence: 99%

“…Our findings will contribute to increasing and strengthening the knowledge on the molecular mechanism of inhibition of HT against α-Syn aggregates, which, in turn, encourage the design of new chemical entities against α-Syn aggregates as well as other aggregating species involved in several chronic neurodegenerative diseases. Recently, the disruption mechanism of α-Syn decamer comprising two intertwined pentamers (PDB ID: 6CU7) by Ellagic acid has been investigated using MD simulations . The computational studies investigating the effect of inhibitors on the destabilization of oligomers of different sizes are worthy for gaining insights into the discovery of new inhibitors of α-Syn aggregation and protofibril destabilization in PD.…”

Section: Introductionmentioning

confidence: 99%

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Unveiling How Hydroxytyrosol Destabilizes α-Syn Oligomers Using Molecular Simulations

Kaur,

Mankoo,

Goyal

et al. 2023

J. Phys. Chem. B

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The etiology of Parkinson’s disease (PD) is mainly linked to the α-synuclein (α-Syn) fibrillogenesis. Hydroxytyrosol (HT), also known as 3,4-dihydroxyphenylethanol, is a naturally occurring polyphenol, found in extra virgin olive oil, and has been shown to have cardioprotective, anticancer, antiobesity, and antidiabetic properties. HT has neuroprotective benefits in neurodegenerative diseases and lessens the severity of PD by reducing the aggregation of α-Syn and destabilizing the preformed toxic α-Syn oligomers. However, the molecular mechanism by which HT destabilizes α-Syn oligomers and alleviates the accompanying cytotoxicity remains unexplored. The impact of HT on the α-Syn oligomer structure and its potential binding mechanism was examined in this work by employing molecular dynamics (MD) simulations. The secondary structure analysis depicted that HT significantly reduces the β-sheet and concomitantly increases the coil content of α-Syn trimer. Visualization of representative conformations from the clustering analysis depicted the hydrogen bond interactions of the hydroxyl groups in HT with the N-terminal and nonamyloid-β component (NAC) region residues of α-Syn trimer, which, in turn, leads to the weakening of interchain interactions in α-Syn trimer and resulted in the disruption of the α-Syn oligomer. The binding free energy calculations depict that HT binds favorably to α-Syn trimer (ΔG binding = −23.25 ± 7.86 kcal/mol) and a notable reduction in the interchain binding affinity of α-Syn trimer on the incorporation of HT, which, in turn, highlights its potential to disrupt α-Syn oligomers. The current research provided mechanistic insights into the destabilization of α-Syn trimer by HT, which, in turn, will provide new clues for developing therapeutics against PD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unveiling How Hydroxytyrosol Destabilizes α-Syn Oligomers Using Molecular Simulations

Kaur,

Mankoo,

Goyal

et al. 2023

J. Phys. Chem. B

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Unravelling the destabilization potential of ellagic acid on α-synuclein fibrils using molecular dynamics simulations

Abstract: The aberrant deposition of α–Synuclein (α–Syn) protein into the intracellular neuronal aggregates termed Lewy bodies and Lewy neurites characterize the devastating neurodegenerative condition known as Parkinson’s disease (PD). The disruption...

Cited by 1 publication

References 98 publications

Unveiling How Hydroxytyrosol Destabilizes α-Syn Oligomers Using Molecular Simulations

Unveiling How Hydroxytyrosol Destabilizes α-Syn Oligomers Using Molecular Simulations

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