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<p>Curcumin is a pleiotropic small molecule proposed to modulate Alzheimer’s disease (AD) pathology; however, its molecular mechanism in destabilizing and inhibiting the aggregation of amyloid-β (Aβ) and tau peptides remains unclear. Here, we integrate molecular docking with 1 µs all-atom molecular dynamics (MD) simulations of representative Aβ and tau protofilaments, in both apo and curcumin-bound states, to quantify structure, dynamics and binding free energies and thereby elucidate curcumin’s inhibitory mechanism at the molecular level. Aβ exhibits greater intrinsic flexibility than tau, while curcumin binding reduced β-sheet content and increased coil, bend, and turn structures, consistent with disrupted β-strand assembly. In tau, curcumin binding at β4 (residues 335–342) and β7 (residues 355–364) sheets of tau induces localized β-sheet disruption, supporting its role in promoting fibril destabilization. Inter-chain hydrogen bonds in Aβ decreased at terminal and central (C–D) interfaces upon curcumin binding, whereas tau displayed increased inter-chain contacts and reduced solvent exposure in the presence of curcumin. Clustering revealed a defined Aβ binding site between β1/β2 strands, while tau interactions were more surface-exposed near β6. Binding free energies favoured Aβ protofibril (− 16.3 ± 0.3&#xa0;kcal·mol⁻¹) over tau (− 6.2 ± 0.2&#xa0;kcal·mol⁻¹), with Aβ interaction driven by van der Waals dispersion and tau binding limited by polar desolvation. Collectively, these findings reveal curcumin preferentially disrupts both Aβ and tau fibrils, with a more pronounced disaggregation effect on Aβ compared to tau, providing molecular-level insights into its differential anti-aggregation potential in AD.</p> Graphical Abstract <p></p>

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Molecular insights into curcumin’s Anti-Alzheimer’s potential through Amyloid-β and Tau interactions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Karnati Ganesh Reddy,
  • Sunandini Swain,
  • Aryan Aryan,
  • Atanu K. Metya

摘要

Curcumin is a pleiotropic small molecule proposed to modulate Alzheimer’s disease (AD) pathology; however, its molecular mechanism in destabilizing and inhibiting the aggregation of amyloid-β (Aβ) and tau peptides remains unclear. Here, we integrate molecular docking with 1 µs all-atom molecular dynamics (MD) simulations of representative Aβ and tau protofilaments, in both apo and curcumin-bound states, to quantify structure, dynamics and binding free energies and thereby elucidate curcumin’s inhibitory mechanism at the molecular level. Aβ exhibits greater intrinsic flexibility than tau, while curcumin binding reduced β-sheet content and increased coil, bend, and turn structures, consistent with disrupted β-strand assembly. In tau, curcumin binding at β4 (residues 335–342) and β7 (residues 355–364) sheets of tau induces localized β-sheet disruption, supporting its role in promoting fibril destabilization. Inter-chain hydrogen bonds in Aβ decreased at terminal and central (C–D) interfaces upon curcumin binding, whereas tau displayed increased inter-chain contacts and reduced solvent exposure in the presence of curcumin. Clustering revealed a defined Aβ binding site between β1/β2 strands, while tau interactions were more surface-exposed near β6. Binding free energies favoured Aβ protofibril (− 16.3 ± 0.3 kcal·mol⁻¹) over tau (− 6.2 ± 0.2 kcal·mol⁻¹), with Aβ interaction driven by van der Waals dispersion and tau binding limited by polar desolvation. Collectively, these findings reveal curcumin preferentially disrupts both Aβ and tau fibrils, with a more pronounced disaggregation effect on Aβ compared to tau, providing molecular-level insights into its differential anti-aggregation potential in AD.

Graphical Abstract