Mechanism of the interaction of toxic SOD1 fibrils with two potent polyphenols: curcumin and quercetin

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease commonly caused due to the aggregation of superoxide dismutase 1 (SOD1) protein. Finding inhibitors of SOD1 aggregation is of prime concern, but understanding the mechanistic action of inhibitors is equally important. Re...

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Bibliographic Details
Published in:Physical chemistry chemical physics : PCCP 2023-08, Vol.25 (34), p.2381-2391
Main Authors: Sharma, Shilpa, Tomar, Vijay Raj, Deep, Shashank
Format: Article
Language:English
Subjects:
Amino acids
Amyotrophic lateral sclerosis
Free energy
Inhibitors
Molecular dynamics
Polyphenols
Superoxide dismutase
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Summary:Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease commonly caused due to the aggregation of superoxide dismutase 1 (SOD1) protein. Finding inhibitors of SOD1 aggregation is of prime concern, but understanding the mechanistic action of inhibitors is equally important. Recent experiments found that two polyphenols, curcumin, and quercetin, have the ability to inhibit SOD1 aggregation. Quercetin was experimentally proven to break pre-formed fibrils into shorter segments, while curcumin did not significantly affect the pre-formed species. Here, we delve deeper into understanding the mechanism of action of quercetin and curcumin on pre-formed octameric fibrils of SOD1 ( 28 PVKVWGSIKGL 38 : chains A-H) with the help of molecular dynamics (MD) simulations of a fibril docked polyphenol complex. Our results suggest that quercetin shows π-π stacking interaction with one of the key residues for toxic amyloid formation, Trp 32 of chains D, E, and F, and breaks the peptide chains G, and H from the rest of the fibril. On the other hand, curcumin binds to the hydrophobic amino acids of almost all the chains B-H and stabilizes the fibril rather than destabilizing it. Binding free energy calculations using MM/PBSA showed that curcumin binds more strongly to the SOD1 fibril due to greater van der Waals interactions compared to quercetin. These findings provide insights for the development of potential ALS treatments. Interactions between octameric SOD1 fibrils and polyphenols, curcumin and quercetin, observed through molecular dynamics simulations.
ISSN:1463-9076
1463-9084
DOI:10.1039/d3cp02120c